InteractiveFly: GeneBrief

Spargel: Biological Overview | References

Gene name - spargel

Synonyms -

Cytological map position - 82B1-82B1

Function - transcription factor

Keywords - fat body; mediation of mitochondrial activity, cell growth and transcription of target genes in response to insulin signalling

Symbol - srl

FlyBase ID: FBgn0037248

Genetic map position - 3R: 248,205..255,051 [-]

Classification - RRM RNA-binding motif

Cellular location - nuclear

NCBI link: EntrezGene
srl orthologs: Biolitmine

Recent literature
Merzetti, E.M. and Staveley, B.E. (2015). spargel, the PGC-1α homologue, in models of Parkinson disease in Drosophila melanogaster. BMC Neurosci 16: 70. PubMed ID: 26502946
Parkinson disease (PD) is a progressive neurodegenerative disorder presenting with symptoms of resting tremor, bradykinesia, rigidity, postural instability and additional severe cognitive impairment over time. These symptoms arise from a decrease of available dopamine in the striatum of the brain resulting from the breakdown and death of dopaminergic (DA) neurons. A process implicated in the destruction of these neurons is mitochondrial breakdown and impairment. Upkeep and repair of mitochondria involves a number of complex and key components including Pink1, Parkin, and the PGC family of genes. PGC-1α has been characterized as a regulator of mitochondria biogenesis, insulin receptor signalling and energy metabolism, mutation of this gene has been linked to early onset forms of PD. The mammalian PGC family consists of three partially redundant genes making the study of full or partial loss of function difficult. The sole Drosophila melanogaster homologue of this gene family, spargel (srl), has been shown to function in similar pathways of mitochondrial upkeep and biogenesis. This study shows that the directed expression of srl-RNAi in the D. melanogaster eye causes abnormal ommatidia and bristle formation while eye specific expression of srl-EY does not produce the minor rough eye phenotype associated with high temperature GMR-Gal4 expression. Ddc-Gal4 mediated tissue specific expression of srl transgene constructs in D. melanogaster DA neurons causes altered lifespan and climbing ability. Expression of a srl-RNAi causes an increase in mean lifespan but a decrease in overall loco-motor ability while induced expression of srl-EY causes a severe decrease in mean lifespan and a decrease in loco-motor ability. The reduced lifespan and climbing ability associated with a tissue specific expression of srl in DA neurons provides a new model of PD in D. melanogaster which may be used to identify novel therapeutic approaches to human disease treatment and prevention.

Merzetti, E. M. and Staveley, B. E. (2015). spargel, the PGC-1alpha homologue, in models of Parkinson disease in Drosophila melanogaster. BMC Neurosci 16: 70. PubMed ID: 26502946
Parkinson disease (PD) is a progressive neurodegenerative disorder that arises from a decrease of available dopamine in the striatum of the brain resulting from the breakdown and death of dopaminergic (DA) neurons. PGC-1alpha has been characterized as a regulator of mitochondria biogenesis, insulin receptor signalling and energy metabolism, mutation of this gene has been linked to early onset forms of PD. The sole Drosophila homologue of this gene family, spargel (srl), has been shown to function in similar pathways of mitochondrial upkeep and biogenesis. Directed expression of srl-RNAi in the Drosophila eye causes abnormal ommatidia and bristle formation while eye specific expression of srl-EY does not produce the minor rough eye phenotype associated with high temperature GMR-Gal4 expression. Ddc-Gal4 mediated tissue specific expression of srl transgene constructs in Drosophila DA neurons causes altered lifespan and climbing ability. Expression of a srl-RNAi causes an increase in mean lifespan but a decrease in overall loco-motor ability while induced expression of srl-EY causes a severe decrease in mean lifespan and a decrease in loco-motor ability. The reduced lifespan and climbing ability associated with a tissue specific expression of srl in DA neurons provides a new model of PD in D. melanogaster which may be used to identify novel therapeutic approaches to human disease treatment and prevention.
Ng, C. H., Basil, A. H., Hang, L., Tan, R., Goh, K. L., O'Neill, S., Zhang, X., Yu, F. and Lim, K. L. (2017). Genetic or pharmacological activation of the Drosophila PGC-1alpha ortholog spargel rescues the disease phenotypes of genetic models of Parkinson's disease. Neurobiol Aging 55: 33-37. PubMed ID: 28407521
Despite intensive research, the etiology of Parkinson's disease (PD) remains poorly understood and the disease remains incurable. However, compelling evidence gathered over decades of research strongly support a role for mitochondrial dysfunction in PD pathogenesis. Related to this, PGC-1&alpha, a key regulator of mitochondrial biogenesis, has recently been proposed to be an attractive target for intervention in PD. This study shows that silencing of expression of the Drosophila PGC-1α ortholog spargel results in PD-related phenotypes in flies and also seems to negate the effects of AMPK activation, which has been previously demonstrated to be neuroprotective; that is, AMPK-mediated neuroprotection appears to require PGC-1alpha. Importantly, this study further showed that genetic or pharmacological activation of the Drosophila PGC-1alpha ortholog spargel is sufficient to rescue the disease phenotypes of Parkin and LRRK2 genetic fly models of PD, thus supporting the proposed use of PGC-1alpha-related strategies for neuroprotection in PD.
Wei, P., Guo, J., Xue, W., Zhao, Y., Yang, J. and Wang, J. (2018). RNF34 modulates the mitochondrial biogenesis and exercise capacity in muscle and lipid metabolism through ubiquitination of PGC-1 in Drosophila. Acta Biochim Biophys Sin (Shanghai) 50(10): 1038-1046. PubMed ID: 30247505
The transcriptional co-activator PGC-1alpha is a key regulator of mitochondrial function and muscle fiber specification in the skeletal muscle. The E3 ubiquitin ligase RNF34 ubiquitinates PGC-1alpha and negatively regulates mammalian brown fat cell metabolism. However, the functional importance of RNF34 in the skeletal muscle and its impact on energy metabolism remain unknown. The Drosophila PGC-1 homolog dPGC-1 and its mammalian counterparts have conserved functions in mitochondria and insulin signaling. This study showed that the Drosophila RNF34 (dRNF34) ubiquitinates the Drosophila PGC-1alpha (dPGC-1) and promotes its degradation in HEK293T cells by immunoprecipitation and western blot analysis. This allows Drosophila to be used as a powerful model system to study the physiological role of RNF34 in mitochondrial function and metabolism. In the in vivo studies, by separately expressing two independent UAS-dRNF34 RNAi transgenes driven by the muscle-specific 24B-Gal4 driver, this study found that knockdown of dRNF34 specifically in muscle promotes mitochondrial biogenesis, improves negative geotaxis, extends climbing time to exhaustion in moderate aged flies and counteracts high-fat-diet-induced high triglyceride content. Furthermore, knockdown of dPGC-1 reversed the effects of the dRNF34 knockdown phenotypes described above. These results reveal that dRNF34 plays an important role in regulating mitochondrial biogenesis in muscle and lipid metabolism through dPGC-1. Thus, inhibition of RNF34 activity provides a potential novel therapeutic strategy for the treatment of age-related muscle dysfunction.
George, J. and Jacobs, H. T. (2019). Minimal effects of spargel (PGC-1) overexpression in a Drosophila mitochondrial disease model. Biol Open 8(7). PubMed ID: 31292108
PGC-1alpha and its homologues have been proposed to act as master regulators of mitochondrial biogenesis in animals. Most relevant studies have been conducted in mammals, where interpretation is complicated by the fact that there are three partially redundant members of the gene family. In Drosophila, only a single PGC-1 homologue, spargel (srl), is present in the genome. This study analyzed the effects of srl overexpression on phenotype and on gene expression in tko25t, a recessive bang-sensitive mutant with a global defect in oxidative phosphorylation, resulting from a deficiency of mitochondrial protein synthesis. In contrast to previous reports, this study found that substantial overexpression of srl throughout development had only minimal effects on the tko25t mutant phenotype. Copy number of mtDNA was unaltered and srl overexpression produced no systematic effects on a representative set of transcripts related to mitochondrial OXPHOS and other metabolic enzymes, although these were influenced by sex and genetic background. This study provides no support to the concept of Spargel as a global regulator of mitochondrial biogenesis, at least in the context of the tko25t model.
Basar, M. A., Williamson, K., Roy, S. D., Finger, D. S., Ables, E. T. and Duttaroy, A. (2019). Spargel/dPGC-1 is essential for oogenesis and nutrient-mediated ovarian growth in Drosophila. Dev Biol. PubMed ID: 31251895
Dietary proteins are crucial for oogenesis. Target of Rapamycin (TOR) is a major nutrient sensor controlling organismal growth and fertility, but the downstream effectors of TOR signaling remain largely uncharacterized. Drosophila Spargel/dPGC-1 has been identified as a terminal effector of the TOR-TSC pathway, and this study now reports that Spargel connects nutrition to oogenesis. Spargel is expressed predominantly in the ovaries of adult flies, and germline spargel knockdown inhibits cyst growth, ultimately leading to egg chamber degeneration and female sterility. In situ staining demonstrated nuclear localization of Spargel in the nurse cells and follicle cells of the ovariole. Furthermore, Spargel/dPGC-1 expression is influenced by dietary yeast concentration and TOR signaling, suggesting Spargel/dPGC-1 might transmit nutrient-mediated signals into ovarian growth. It is proposed that potentiating Spargel/dPGC-1 expression in the ovary is instrumental in nutrient-mediated regulation of oogenesis.
George, J. and Jacobs, H. T. (2019). Germline knockdown of spargel (PGC-1) produces embryonic lethality in Drosophila. Mitochondrion. PubMed ID: 31473309
The PGC-1 transcriptional coactivators have been proposed as master regulators of mitochondrial biogenesis and energy metabolism. This study shows that the single member of the family in Drosophila, spargel (srl) has an essential role in early development. Female germline-specific RNAi knockdown resulted in embryonic semilethality. Embryos were small, with most suffering a catastrophic derangement of cellularization and gastrulation, although genes dependent on localized determinants were expressed normally. The abundance of mtDNA, representative mitochondrial proteins and mRNAs were not decreased in knockdown ovaries or embryos, indicating that srl has a more general role in early development than specifically promoting mitochondrial biogenesis.
Wen, D. T., Zheng, L., Li, J. X., Cheng, D., Liu, Y., Lu, K. and Hou, W. Q. (2019). Endurance exercise resistance to lipotoxic cardiomyopathy is associated with cardiac NAD(+)/dSIR2/PGC-1alpha pathway activation in old Drosophila. Biol Open 8(10). PubMed ID: 31624074
Lipotoxic cardiomyopathy is caused by excessive lipid accumulation in myocardial cells and it is a form of cardiac dysfunction. Cardiac PGC-1alpha overexpression prevents lipotoxic cardiomyopathy induced by a high-fat diet (HFD). The level of NAD(+) and Sir2 expression upregulate the transcriptional activity of PGC-1alpha. Exercise improves cardiac NAD(+) level and PGC-1alpha activity. However, the relationship between exercise, NAD(+)/dSIR2/PGC-1alpha pathway and lipotoxic cardiomyopathy remains unknown. In this study, flies were fed a HFD and exercised. The heart dSir2 gene was specifically expressed or knocked down by UAS/hand-Gal4 system. The results showed that either a HFD or dSir2 knockdown remarkably increased cardiac TG level and dFAS expression, reduced heart fractional shortening and diastolic diameter, increased arrhythmia index, and decreased heart NAD(+) level, dSIR2 protein, dSir2 and PGC-1alpha expression levels. Contrarily, either exercise or dSir2 overexpression remarkably reduced heart TG level, dFAS expression and arrhythmia index, and notably increased heart fractional shortening, diastolic diameter, NAD(+) level, dSIR2 level, and heart dSir2 and PGC-1alpha expression. Therefore, exercise training could improve lipotoxic cardiomyopathy induced by a HFD or cardiac dSir2 knockdown in old Drosophila. The NAD(+)/dSIR2/PGC-1alpha pathway activation was an important molecular mechanism of exercise resistance against lipotoxic cardiomyopathy.
Wang, Q. P., Lin, Y. Q., Lai, M. L., Su, Z., Oyston, L. J., Clark, T., Park, S. J., Khuong, T. M., Lau, M. T., Shenton, V., Shi, Y. C., James, D. E., Ja, W. W., Herzog, H., Simpson, S. J. and Neely, G. G. (2020). PGC1alpha Controls Sucrose Taste Sensitization in Drosophila. Cell Rep 31(1): 107480. PubMed ID: 32268099
Perceived palatability of food controls caloric intake. Sweet taste is the primary means of detecting the carbohydrate content of food. Surprisingly, sweet taste sensitivity is responsive to extrinsic factors like diet, and this occurs by unknown mechanisms. This study describes an unbiased proteomic investigation into sweet taste sensitivity in the fruit fly. A dopamine/cyclic AMP (cAMP)/CREB axis acting within sweet taste neurons that controls taste perception but is largely dispensable for acute taste transduction. This pathway modulates sweet taste perception in response to both sensory- and nutrient-restricted diets and converges on PGC1alpha, a critical regulator of metabolic health and lifespan. By electrophysiology, it was found that enhanced sucrose taste sensitivity was the result of heightened sweet taste intensity and that PGC1alpha was both necessary and sufficient for this effect. Together, this study provides the first molecular insight into how diet-induced taste perception is regulated within the sweet taste neuron.
Cobb, T., Damschroder, D. and Wessells, R. (2021). Sestrin regulates acute chill coma recovery in Drosophila melanogaster. Insect Biochem Mol Biol: 103548. PubMed ID: 33549817
When chill-susceptible insects are exposed to low temperatures they enter a temporary state of paralysis referred to as a chill coma. The most well-studied physiological mechanism of chill coma onset and recovery involves regulation of ion homeostasis. Previous studies show that changes in metabolism may also underlie the ability to recovery quickly, but the roles of genes that regulate metabolic homeostasis in chill coma recovery time (CCRT) are not well understood. This study investigated the roles of Sestrin and Spargel (Drosophila homolog of PGC-1α), which are involved in metabolic homeostasis and substrate oxidation, on CCRT in Drosophila melanogaster. sestrin and spargel mutants have impaired CCRT. sestrin is required in the muscle and nervous system tissue for normal CCRT and spargel is required in muscle and adipose. On the basis that exercise induces sestrin and spargel, the interaction of cold and exercise was tested. Pre-treatment with one of these stressors does not consistently confer acute protection against the other. It is concluded that Sestrin and Spargel are important in the chill coma response, independent of their role in exercise.
Millington, J. W., Brownrigg, G. P., Chao, C., Sun, Z., Basner-Collins, P. J., Wat, L. W., Hudry, B., Miguel-Aliaga, I. and Rideout, E. J. (2021). Female-biased upregulation of insulin pathway activity mediates the sex difference in Drosophila body size plasticity. Elife 10. PubMed ID: 33448263
Nutrient-dependent body size plasticity differs between the sexes in most species, including mammals. Previous work in Drosophila showed that body size plasticity was higher in females, yet the mechanisms underlying increased female body size plasticity remain unclear. This study discovered that a protein-rich diet augments body size in females and not males because of a female-biased increase in activity of the conserved insulin/insulin-like growth factor signaling pathway (IIS). This sex-biased upregulation of IIS activity was triggered by a diet-induced increase in stunted mRNA in females, and required Drosophila insulin-like peptide 2, illuminating new sex-specific roles for these genes. Importantly, this study shows that sex determination gene transformer promotes the diet-induced increase in stunted mRNA via transcriptional coactivator Spargel to regulate the male-female difference in body size plasticity. Together, these findings provide vital insight into conserved mechanisms underlying the sex difference in nutrient-dependent body size plasticity.
Sujkowski, A. and Wessells, R. (2021). Exercise and Sestrin Mediate Speed and Lysosomal Activity in Drosophila by Partially Overlapping Mechanisms. Cells 10(9). PubMed ID: 34572128
Chronic exercise is widely recognized as an important contributor to healthspan in humans and in diverse animal models. Recently, it has been demonstrated that Sestrins, a family of evolutionarily conserved exercise-inducible proteins, are critical mediators of exercise benefits in flies and mice. Knockout of Sestrins prevents exercise adaptations to endurance and flight in Drosophila, and similarly prevents benefits to endurance and metabolism in exercising mice. In contrast, overexpression of dSestrin in muscle mimics several of the molecular and physiological adaptations characteristic of endurance exercise. This study extended those observations to examine the impact of dSestrin on preserving speed and increasing lysosomal activity. dSestrin was found to be a critical factor driving exercise adaptations to climbing speed, but is not absolutely required for exercise to increase lysosomal activity in Drosophila. The role of Sestrin in increasing speed during chronic exercise requires both the TORC2/AKT axis and the PGC1α homolog Spargel, while dSestrin requires interactions with TORC1 to cell-autonomously increase lysosomal activity. These results highlight the conserved role of Sestrins as key factors that drive diverse physiological adaptations conferred by chronic exercise.
Groen, C. M., Podratz, J. L., Pathoulas, J., Staff, N. and Windebank, A. J. (2021). Genetic Reduction of Mitochondria Complex I Subunits is Protective Against Cisplatin-Induced Neurotoxicity in Drosophila. J Neurosci. PubMed ID: 34893548
Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent side effect of widely used platinum-based anti-cancer agents. There are few predictable risk factors to identify susceptible patients. Effective preventive measures or treatments are not available. This study used a model of CIPN in Drosophila melanogaster to identify genetic changes that confer resistance to cisplatin-induced neuronal damage but not in the rapidly dividing cells of the ovary. The Drosophila strain attP40, used as a genetic background for creation of RNAi lines, is resistant to cisplatin damage compared to the similar attP2 background strain. attP40 flies have reduced mRNA expression of ND-13A, a component of the mitochondria electron transport chain complex I. Reduction of ND-13A via neuron-specific RNAi leads to resistance to the dose-dependent climbing deficiencies and neuronal apoptosis observed in control flies. These flies are also resistant to acute oxidative stress, suggesting a mechanism for resistance to cisplatin. The mitochondria of attP40 flies function similarly to control attP2 mitochondria under normal conditions. Mitochondria are damaged by cisplatin, leading to reduced activity, but attP40 mitochondria are able to retain function and even increase basal respiration rates in response to this stress. This retained mitochondrial activity is likely mediated by Sirt1 and PGC1α, and is key to cisplatin resistance. These findings represent potential for both identification of susceptible patients and prevention of CIPN through the targeting of mitochondria.
Damschroder, D., Zapata-Perez, R., Richardson, K., Vaz, F. M., Houtkooper, R. H. and Wessells, R. (2022). Stimulating the sir2-pgc-1alpha axis rescues exercise capacity and mitochondrial respiration in Drosophila tafazzin mutants. Dis Model Mech. PubMed ID: 36107830
Cardiolipin (CL) is a phospholipid required for proper mitochondrial function. Tafazzin remodels CL to create highly unsaturated fatty acid chains. However, when tafazzin is mutated, CL remodeling is impeded, leading to mitochondrial dysfunction and the disease Barth syndrome. Patients with Barth syndrome often have severe exercise intolerance, which negatively impacts their overall quality of life. Boosting NAD+ levels can improve symptoms of other mitochondrial diseases, but its effect in the context of Barth syndrome has not been examined. This study demonstrates for the first time that nicotinamide riboside (NR) can rescue exercise tolerance and mitochondrial respiration in a Drosophila tafazzin mutant and that the beneficial effects are dependent on sir2 and pgc-1α. Overexpressing pgc-1α increased the total abundance of cardiolipin in mutants. In addition, muscles and neurons were identified as key targets for future therapies because sir2 or pgc-1α overexpression in either of these tissues is sufficient to restore the exercise capacity of Drosophila tafazzin mutants.
Taslim, T. H., Hussein, A. M., Keshri, R., Ishibashi, J. R., Chan, T. C., Nguyen, B. N., Liu, S., Brewer, D., Harper, S., Lyons, S., Garver, B., Dang, J., Balachandar, N., Jhajharia, S., Castillo, D. D., Mathieu, J. and Ruohola-Baker, H. (2023). Stress-induced reversible cell-cycle arrest requires PRC2/PRC1-mediated control of mitophagy in Drosophila germline stem cells and human iPSCs. Stem Cell Reports 18(1): 269-288. PubMed ID: 36493777
Following acute genotoxic stress, both normal and tumorous stem cells can undergo cell-cycle arrest to avoid apoptosis and later re-enter the cell cycle to regenerate daughter cells. However, the mechanism of protective, reversible proliferative arrest, "quiescence," remains unresolved. This study shows that mitophagy is a prerequisite for reversible quiescence in both irradiated Drosophila germline stem cells (GSCs) and human induced pluripotent stem cells (hiPSCs). In GSCs, mitofission (Drp1) or mitophagy (Pink1/Parkin) genes are essential to enter quiescence, whereas mitochondrial biogenesis (PGC1α) or fusion (Mfn2) genes are crucial for exiting quiescence. Furthermore, mitophagy-dependent quiescence lies downstream of mTOR- and PRC2-mediated repression and relies on the mitochondrial pool of cyclin E. Mitophagy-dependent reduction of cyclin E in GSCs and in hiPSCs during mTOR inhibition prevents the usual G1/S transition, pushing the cells toward reversible quiescence (G0). This alternative method of G1/S control may present new opportunities for therapeutic purposes.
Wen, D. T., Gao, Y. H., Wang, J., Wang, S., Zhong, Q. and Hou, W. Q. (2023). Role of muscle FOXO gene in exercise against the skeletal muscle and cardiac age-related defects and mortality caused by high-salt intake in Drosophila. Genes Nutr 18(1): 6. PubMed ID: 36997839
FOXO has long been associated with aging, exercise, and tissue homeostasis, but it remains unclear what the role is of the muscle FOXO gene in exercise (E) against high-salt intake(HSI)-induced age-related defects of the skeletal muscle, heart, and mortality. In this research, overexpression and RNAi of the FOXO gene in the skeletal and heart muscle of Drosophila were constructed by building Mhc-GAL4/FOXO-UAS-overexpression and Mhc-GAL4/FOXO-UAS-RNAi system. The skeletal muscle and heart function, the balance of oxidation and antioxidant, and mitochondrial homeostasis were measured. The results showed that exercise reversed the age-related decline in climbing ability and downregulation of muscle FOXO expression induced by HSI. Muscle-specific FOXO-RNAi (FOXO-RNAi) and -overexpression (FOXO-OE) promoted or slowed the age-related decline in climbing ability, heart function, and skeletal muscle and heart structure damage, which was accompanied by the inhibition or activation of FOXO/PGC-1α/SDH and FOXO/SOD pathway activity, and oxidative stress (ROS) increased or decreased in both skeletal muscle and heart. The protective effect of exercise on the skeletal muscle and heart was blocked by FOXO-RNAi in aged HSI flies. FOXO-OE prolonged its lifespan, but it did not resist the HSI-induced lifespan shortening. Exercise did not improve HSI-induced lifespan shortening in FOXO-RNAi flies. Therefore, current results confirmed that the muscle FOXO gene played a vital role in exercise against age-related defects of the skeletal muscle and heart induced by HSI because it determined the activity of muscle FOXO/SOD and FOXO/PGC-1α/SDH pathways. The muscle FOXO gene also played an important role in exercise against HSI-induced mortality in aging flies.
Roy, S. D., Nagarajan, S., Jalal, M. S., Basar, M. A. and Duttaroy, A. (2023). New mutant alleles for Spargel/dPGC-1 highlights the function of Spargel RRM domain in oogenesis and expands the role of Spargel in embryogenesis and intracellular transport. G3 (Bethesda). PubMed ID: 37369430
Energy metabolism in vertebrates is controlled by three members of the PGC-1 (PPAR γ- coactivator 1) family, transcriptional coactivators that shape responses to physiological stimuli by interacting with the nuclear receptors and other transcription factors. Multiple evidence now supports that Spargel protein found in insects and ascidians is the ancestral form of vertebrate PGC-1's. This study undertook functional analysis of srl gene in Drosophila, asking about the requirement of Spargel per se during embryogenesis and its RNA binding domains. CRISPR- engineered srl gene deletion turned out to be an amorphic allele that is late embryonic/early larval lethal and Spargel protein missing its RNA binding domain (SrlĪ”RRM) negatively affects female fertility. Overexpression of wild-type Spargel in transgenic flies expedited the growth of egg chambers. On the other hand, oogenesis is blocked in a dominant-negative fashion in the presence of excess Spargel lacking its RRM domains. Finally, aggregation of Notch proteins was observed in egg chambers of srl mutant flies, suggesting that Spargel is involved in intracellular transport of Notch proteins. Taken together, this study claims that these new mutant alleles of spargel are emerging powerful tools for revealing new biological functions for Spargel, an essential transcription coactivator in both Drosophila and mammals.


Mitochondrial mass and activity must be adapted to tissue function, cellular growth and nutrient availability. In mammals, the related transcriptional coactivators PGC-1α, PGC-1β, (Peroxisome proliferator-activated receptor gamma coactivator 1-α and -β) and PRC (PGC-1-related coactivator) regulate multiple metabolic functions, including mitochondrial biogenesis. However, relatively little is known about their respective roles in vivo. This study shows that the Drosophila PGC-1 family homologue, Spargel, is required for the expression of multiple genes encoding mitochondrial proteins. Accordingly, spargel mutants showed mitochondrial respiration defects when complex II of the electron transport chain was stimulated. Spargel, however, was not limiting for mitochondrial mass, but functioned in this respect redundantly with Delg, the fly NRF-2α/GABPα homologue. More importantly, in the larval fat body, Spargel mediates mitochondrial activity, cell growth and transcription of target genes in response to insulin signalling. In this process, Spargel functions in parallel to the insulin-responsive transcription factor, dFoxo, and provides a negative feedback loop to fine-tune insulin signalling. Taken together, these data place Spargel at a nodal point for the integration of mitochondrial activity to tissue and organismal metabolism and growth (Tiefenböck, 2010).

As animals grow, nutrients are taken up, leading to an increase in cellular mass. In this process, mitochondria have critical anabolic and catabolic functions in metabolizing nutrients and in adapting cellular physiology. Therefore, one would expect coordination of mitochondrial mass and activity with growth-promoting pathways and nutrient availability, yet this remains poorly understood. To study mitochondrial biogenesis, most studies focused on individual tissues that show an enormous increase in mitochondrial mass in response to external stimuli, for example, during the formation of the brown adipose tissue (BAT) or perinatal heart maturation. Such studies led to identification and characterization of the PGC-1 family of transcriptional coactivators, which are potent inducers of mitochondrial biogenesis: the founding member PGC-1α (PPARγ coactivator 1; Puigserver, 1998), as well as its homologues PGC-1β (Kamei, 2003) and PRC (PGC-1-related coactivator; Andersson, 2001). Mice lacking PGC-1α or PGC-1β showed reduced expression of multiple genes encoding mitochondrial proteins, yet mitochondrial mass and respiration activity were either not or only modestly reduced, depending on the tissue (Lin, 2004; Leone, 2005; Lelliott, 2006; Sonoda, 2007). These mild phenotypes could be because of redundancy. Indeed, RNAi-mediated downregulation of PGC-1β in a PGC-1α-/- background led to strong additive respiration defects in adipocytes (Uldry, 2006). Similarly, mice lacking both PGC-1α and PGC-1β showed defective mitochondrial biogenesis in the heart and the BAT (Lai, 2008). Although these studies clearly demonstrated critical functions for these proteins in mitochondria-rich tissues, a triple knockout of PGC-1α, PGC-1β and PRC has not been published; therefore it remains unclear whether PGC-1s are generally required for basal mitochondrial mass (Tiefenböck, 2010).

PGC-1 family members drive mitochondrial biogenesis through coactivation of nuclear transcription factors, including nuclear respiratory factor-1 and -2 (NRF-1 and NRF-2), estrogen-related receptor-α (ERRα) and YY1, to enhance the expression of genes encoding mitochondrial proteins (Puigserver, 2003; Scarpulla, 2008). Accordingly, NRF-1 and ERRα are known to be functionally important for PGC-1s to stimulate mitochondrial mass (Wu, 1999; Mootha, 2004; Schreiber, 2004). Similarly, NRF-2 promoter-binding sites were required for coactivation by PGC-1α and PRC in certain genes (Gleyzer, 2005), and PRC can coactivate NRF-2β (Vercauteren, 2008). However, it is not known whether NRF-2 is required for PGC-1's effect on mitochondrial function, or whether NRF-2 is controlled through other factors (Tiefenböck, 2010).

In flies and mammals, insulin signalling and TOR (target of rapamycin) function are known to link cellular growth and metabolism to nutrition. Recent data showed that mammalian TOR (mTOR) and mitochondrial oxidative capacity are tightly linked, and mTOR inhibition reduced the association of PGC-1α with the transcription factor YY1, leading to lower expression of several genes encoding mitochondrial proteins (Cunningham, 2007). These data demonstrate that mTOR is a crucial regulator of mitochondrial function in mammals. In flies, nutrient starvation and subsequent inhibition of insulin signalling led to reduced expression of multiple genes encoding mitochondrial proteins. However, a direct role of TOR has not been addressed in these studies. Moreover, the majority of genes encoding mitochondrial proteins were not responsive to TOR inhibition in Drosophila cells. Therefore, mechanisms in addition to TOR must exist to adapt mitochondrial mass and function to nutrient availability (Tiefenböck, 2010).

This study investigated the role of the Drosophila PGC-1 homologue Spargel/CG9809 in the control of mitochondrial biogenesis and activity. The Drosophila genome encodes a single PGC-1 homologue (Gershman, 2007), thus providing a system in which PGC-1 function can be analysed without interfering redundancy. Focused was placed on the larval fat body, the functional equivalent of the mammalian adipose tissue and liver. In this tissue, many genes encoding mitochondrial proteins were expressed in a nutrient-sensitive manner (Teleman, 2008; Baltzer, 2009). The larval fat body is, therefore, ideal to study how mitochondrial mass and activity are coordinated with cellular metabolism and nutrient supply. This study shows that Spargel is required for proper expression of most genes encoding mitochondrial proteins. When complex II of the electron transport chain is stimulated, spargel mutants show respiration defects. Remarkably, Spargel is not required for basal mitochondrial mass, but becomes limiting in the absence of Delg, the fly NRF-2α homologue. Moreover, from these and previous experiments (Baltzer, 2009), Spargel and Delg were shown to function in two different pathways, each regulating mitochondrial in response to nutrients. Finally, the question how insulin signalling affected mitochondria was addressed; Spargel was found to be required for the stimulation of mitochondrial respiration, and to a large extent for the transcriptional control mediated by insulin signalling, including that of genes encoding mitochondrial proteins. Moreover, insulin signalling induces Spargel gene expression and protein levels, and Spargel mediates a negative feedback loop on insulin signalling. These data demonstrate a critical role for Spargel in the coordination of mitochondria with nutrients, and thus in cellular metabolism (Tiefenböck, 2010).

The D. melanogaster genome encodes a single PGC-1 homologue, CG9809 (Gershman, 2007). Sequence alignments have shown that the N-terminal acidic domain that mediates transcriptional coactivation for mammalian PGC-1s, and the C-terminal arginine-serine-rich and RNA recognition domains are highly conserved in the fly protein (Gershman, 2007), yet its cellular function has not been addressed. To test whether CG9809 is a functional PGC-1 homologue in flies, mutants that have a P-element insertion (KG08646) in the 5' UTR were examined. In comparison with controls (precise excision of the P-element), homozygous mutant larvae had a strong reduction in CG9809 mRNA levels, adults were viable, and females were sterile. Both males and females had a 25% reduction in wet weight, which correlated with reduced protein, lipid, glycogen and trehalose levels per animal. When normalized to body weight, reduced lipid and glycogen levels were observed in adult males, demonstrating metabolic defects. When external structures that are derived from imaginal discs were analysed, such as wings or legs, no large size defects were detected in CG9809 mutants. These animals have, therefore, a lean phenotype, prompting use of the name 'Spargel' German for 'asparagus', and the KG08646 allele as srl1. To test the specificity of this allele, a second P-element insertion (d04518, termed srl2), was tested; this showed the same phenotypes as srl1 and transgenic flies were created carrying a genomic rescue construct, which suppressed all mutant phenotypes. As another gene, CG31525, is located within the first intron of Spargel, a fly line was created expressing a Spargel cDNA under the control of the UAS promoter. When driven using heat-shock Gal4, UAS-Srl also suppressed the mutant phenotypes, demonstrating that loss of Spargel function was responsible for the observed phenotypes. Finally, a trans-heterozygous combination of srl1 with Df(3R)ED5046, a deficiency that deletes the Spargel locus, led to a further reduction in Spargel transcript levels, yet it did not lead to a further decrease in adult weight compared with srl1 homozygous mutant animals. Taken together, srl1 is a strong hypomorphic allele, showing a ~75% reduction in mRNA levels (Tiefenböck, 2010).

Mitochondrial mass and activity must adapt to cellular growth rates and nutrient availability, yet factors involved were poorly described. This study showed that Drosophila Spargel is critical for proper expression of genes encoding mitochondrial proteins, and that it mediates a link to the nutrient-sensitive insulin signalling pathway. In the larval fat body, Spargel was required for proper mitochondrial respiration when complex II was stimulated, both under normal and insulin signalling stimulated conditions. These data support the interpretation that the control of mitochondria represents an ancestral function of the PGC-1 proteins family. Importantly, it was shown that Spargel is not a master regulator of mitochondrial biogenesis, but becomes limiting in this respect in the absence of Delg. Furthermore, ectopic expression of Spargel was not sufficient to drive mitochondrial abundance, which contrasts mammalian data, where PGC-1's are potent stimulators of mitochondrial mass. Mammalian PGC-1 proteins are induced by external stimuli, including cold exposure in BAT or exercise in muscle tissues, thus adapting the cellular physiology in response to such stimuli (Puigserver, 2003). To test a similar function for Drosophila Spargel, larvae were exposed to cold shocks, and respiration rates from dissected fat bodies were measured by complex I stimulation. Although cold exposure led to reduced respiration, this response was not altered in the spargel mutant. Thus this function is not conserved in flies, which correlates with previous findings that the Drosophila fat body resembles the mammalian white adipose tissue, which is not involved in thermoregulation (Baltzer, 2009). Furthermore, genes involved in gluconeogenesis, β-oxidation and lipogenesis, all functions linked to mammalian PGC-1 proteins (Lin, 2005), were not reduced in the spargel mutant, at least not in the larval fat body. No altered lipid levels were detected in spargel mutant larvae, thus these functions might be vertebrate-specific. Potentially, these differences can be explained by the finding that Spargel lacks the canonical LXXLL motifs, which mediate binding to multiple transcription factors for mammalian PGC-1s (Gershman, 2007). Spargel however contains a conserved C-terminal FXXLL motif (Gershman, 2007), which could mediate transcription factor binding, yet such interactors remain elusive (Tiefenböck, 2010).

In mammalian cells, overexpression of PGC-1α led to increased expression of NRF-2α/GABPα (Mootha, 2004), and NRF-2 binding sites in the promoters of mitochondrial transcription factors TFB1M and TFB2M were required for coactivation by PGC-1α and PRC (Gleyzer, 2005). Similarly, PRC was shown to coactivate NRF-2β-dependent transcription (Vercauteren, 2008), thus it was assumed that PGC-1 proteins and NRF-2 would function in the same pathway. Very importantly, these studies focused on individual genes, but not on mitochondrial function and mass, thus it is still unclear whether NRF-2 is functionally required for PGC-1 proteins in respect to mitochondrial mass. Although Drosophila Spargel and Delg may share many putative target genes, these factors function in parallel pathways in respect to mitochondrial mass, morphology and OXPHOS activity (Tiefenböck, 2010).

The respiration defects in spargel single mutants can be explained by reduced expression of genes involved in oxidative phosphorylation. Spargel mutants however did not show a reduction in mitochondrial abundance, which appears surprising. In wild-type larvae, the fat body does not attract tracheoles for gas exchange, and shows physiological low oxygen levels, suggesting low rates of mitochondrial respiration. Indeed, compared to other larval tissues, a low inner-mitochondrial membrane potential and reduced oxygen consumption was detected (Baltzer, 2009). This suggests that oxidative phosphorylation might not be a critical function of the fat body mitochondria. Rather, this tissue releases lipids and amino acids, in particular proline and glutamine, providing energy sources for other tissues. Since proline and glutamine are synthesized from the mitochondrial TCA cycle intermediate 2-oxoglutarate, it is proposed that such a function is rate limiting for mitochondrial mass in the fat body. Delg but not Spargel was required for proper expression of genes involved in proline and glutamine metabolism (Baltzer, 2009), thus explaining the mitochondrial abundance defect in the delg mutant, and the absence of such defects in the spargel mutant (Tiefenböck, 2010).

Spargel and Delg are distinct in respect to upstream signalling: Spargel is functionally required for insulin signalling, which was not seen for Delg. In contrast, Delg, but not Spargel, is required for Cyclin D/Cdk4 to stimulate mitochondrial abundance (Baltzer, 2009). Thus the data provided genetic evidence that Spargel and Delg represent two different pathways, each regulating mitochondria in response to nutrients. Although several recent reports have demonstrated a functional link between insulin signalling and PGC-1 proteins in mammalian cells, the interaction appears to be complex, and is most likely tissue and/or context dependent: Some studies showed that PGC-1 proteins were required for insulin signalling (Vianna, 2006; Pagel-Langenickel, 2008), whereas other studies found an inhibitory function for PGC-1α (Koo, 2004; Choi, 2008). In flies, the insulin signalling pathway is well conserved, and since Spargel is the only PGC-1 protein, Drosophila is an ideal organism to study a functional interaction between insulin signalling and PGC-1 proteins in vivo (Tiefenböck, 2010).

Spargel is required for insulin signalling stimulated growth, functioning downstream of Dp110, but presumably independently of Akt, and balances signalling activity through a negative-feedback loop. Very remarkably, Spargel mediates ~40% of the transcriptional control in response to insulin signalling, emphasizing a major function in the control of cellular growth and metabolism. Moreover, these data suggest that Spargel functions independently of dFoxo, therefore representing a novel transcriptional output of insulin signalling in the larval fat body. This appears to contradict recent microarray data, which showed repressed Spargel mRNA levels upon expression of an activated form of dFoxo in culture Drosophila cells (Gershman, 2007). The discrepancy could be due to tissue-inherent differences. In this study, INR expression led to an increase in Spargel mRNA and protein abundance, further suggesting that Spargel has a direct role within the insulin signalling pathway. Future experiments are required to establish a molecular mechanism how Spargel function and subcellular localization is mediated by insulin signalling components. Analogous to the current results, reduced PGC-1α protein levels were observed upon knockdown of the insulin receptor InsRβ in mammalian cells (Pagel-Langenickel, 2008), suggesting a conserved mechanism between flies and mammals. Thus the data are further genetic evidence for a functional interaction between PGC-1 proteins and insulin signalling. Although flies and mammals are several hundred millions apart in evolution, Spargel and its mammalian counterparts PGC-1α, PGC1-1β and PRC have conserved functions in respect to mitochondria and insulin signalling. In the future, this will allow use of Drosophila as a powerful system to understand regulatory circuitries that control homeostasis of cellular metabolism (Tiefenböck, 2010).

Increased mitochondrial biogenesis preserves intestinal stem cell homeostasis and contributes to longevity in Indy mutant flies

The Drosophila Indy (I'm not dead yet) gene encodes a plasma membrane transporter of Krebs cycle intermediates, with robust expression in tissues associated with metabolism. Reduced INDY alters metabolism and extends longevity in a manner similar to caloric restriction (CR); however, little is known about the tissue specific physiological effects of INDY reduction. This study focused on the effects of INDY reduction in the Drosophila midgut due to the importance of intestinal tissue homeostasis in healthy aging and longevity. The expression of Indy mRNA in the midgut changes in response to aging and nutrition. Genetic reduction of Indy expression increases midgut expression of the mitochondrial regulator spargel/dPGC-1, which is accompanied by increased mitochondrial biogenesis and reduced reactive oxygen species (ROS). These physiological changes in the Indy mutant midgut preserve intestinal stem cell (ISC) homeostasis and are associated with healthy aging. Genetic studies confirm that dPGC-1 mediates the regulatory effects of INDY, as illustrated by lack of longevity extension and ISC homeostasis in flies with mutations in both Indy and dPGC1. These data suggest INDY may be a physiological regulator that modulates intermediary metabolism in response to changes in nutrient availability and organismal needs by modulating dPGC-1 (Rogers, 2014).

Caloric restriction (CR) extends lifespan in nearly all species and promotes organismal energy balance by affecting intermediary metabolism and mitochondrial biogenesis. Interventions that alter intermediary metabolism are though to extend longevity by preserving the balance between energy production and free radical production Indy (I'm Not Dead Yet) encodes a plasma membrane protein that transports Krebs' cycle intermediates across tissues associated with intermediary metabolism. Reduced Indy-mediated transport extends longevity in worms and flies by decreasing the uptake and utilization of nutrients and altering intermediate nutrient metabolism in a manner similar to CR. Furthermore, it was shown that caloric content of food directly affects Indy expression in fly heads and thoraces, suggesting a direct relationship between INDY and metabolism (Rogers, 2014 and references therein).

dPGC-1/spargel is the Drosophila homolog of mammalian PGC-1, a transcriptional co-activator that promotes mitochondrial biogenesis by increasing the expression of genes encoding mitochondrial proteins. Upregulation of dPGC-1 is a hallmark of CR-mediated longevity and is thought to represent a response mechanism to compensate for energetic deficits caused by limited nutrient availability. Increases in dPGC-1 preserve mitochondrial functional efficiency without consequential changes in ROS. Previous analyses of Indy mutant flies revealed upregulation of mitochondrial biogenesis mediated by increased levels of dPGC-1 in heads and thoraces (Rogers, 2014 and references therein).

Recently, dPGC-1 upregulation in stem and progenitor cells of the digestive tract was shown to preserve intestinal stem cell (ISC) proliferative homeostasis and extend lifespan. The Drosophila midgut is regenerated by multipotent ISCs, which replace damaged epithelial tissue in response to injury, infection or changes in redox environment. Low levels of reactive oxygen species (ROS) maintain stemness, self-renewal and multipotency in ISCs; whereas, age-associated ROS accumulation induces continuous activation marked by ISC hyper-proliferation and loss of intestinal integrity (Rogers, 2014 and references therein).

This study describes a role for Indy as a physiological regulator that modulates expression in response to changes in nutrient availability. This is illustrated by altered Indy expression in flies following changes in caloric content and at later ages suggesting that INDY-mediated transport is adjusted in an effort to meet energetic demands. Further, role was characterized for dPGC-1 in mediating the downstream regulatory effects of INDY reduction, such as the observed changes in Indy mutant mitochondrial physiology, oxidative stress resistance and reduction of ROS levels. Longevity studies support a role for dPGC-1 as a downstream effector of Indy mutations as shown by overlapping longevity pathways and absence of lifespan extension without wild-type levels of dPGC-1. These findings show that Indy mutations affect intermediary metabolism to preserve energy balance in response to altered nutrient availability, which by affecting the redox environment of the midgut promotes healthy aging (Rogers, 2014).

Reduction of Indy gene activity in fruit flies, and homologs in worms, extends lifespan by altering energy metabolism in a manner similar to caloric restriction (CR). Indy mutant flies on regular food share many characteristics with CR flies and do not have further longevity extension when aged on a CR diet. Furthermore, mINDY-/- mice on regular chow share 80% of the transcriptional changes observed in CR mice, supporting a conserved role for INDY in metabolic regulation that mimics CR and promotes healthy aging. This study shifted from systemic to the tissue specific effects of INDY reduction, focusing on the midgut due to the high levels of INDY protein expression in wild type flies and the importance of regulated intestinal homeostasis during aging. The evidence supports a role for INDY as a physiological regulator that senses changes in nutrient availability and alters mitochondrial physiology to sustain tissue-specific energetic requirements (Rogers, 2014).

The age-associated increase in midgut Indy mRNA levels that can be replicated by manipulations that accelerate aging such as increasing the caloric content of food or exposing flies to paraquat. Conversely, it was also shown that CR decreases Indy mRNA in control midgut tissues, which is consistent with previous findings in fly muscle and mouse liver. Diet-induced variation in midgut Indy expression suggests that INDY regulates intermediary metabolism by modifying citrate transport to meet tissue or cell-specific bioenergetic needs. Specifically, as a plasma membrane transporter INDY can regulate cytoplasmic citrate, thereby affecting fat metabolism, respiration, and via conversion to malate, the TCA cycle. Reduced INDY-mediated transport activity in the midgut could prevent age-related ISC-hyperproliferation by decreasing the available energy needed to initiate proliferation, thereby preserving tissue function during aging. This is supported by findings that nutrient availability affects ISC proliferation in adult flies and that CR can affect stem cell quiescence and activation (Rogers, 2014).

One of the hallmarks of CR-mediated longevity extension is increased mitochondrial biogenesis mediated by dPGC-1 (Spargel). Increased dPGC-1 levels and mitochondrial biogenesis have been described in the muscle of Indy mutant flies, the liver of mIndy-/- mice, and this study describes it in the midgut of Indy mutant flies. One possible mechanism for these effects can be attributed to the physiological effects of reduced INDY transport activity. Reduced INDY-mediated transport activity could lead to reduced mitochondrial substrates, an increase in the ADP/ATP ratio, activation of AMPK, and dPGC-1 synthesis. This is consistent with findings in CR flies and the livers of mINDY-/- mice. This study's analysis of mitochondrial physiology in the Indy mutant midgut shows upregulation of respiratory proteins, maintenance of mitochondrial potential and increased mitochondrial biogenesis, all of which are signs of enhanced mitochondrial health. The observed increase in dPGC-1 levels in Indy mutant midgut therefore appears to promote mitochondrial biogenesis and functional efficiency, representing a protective mechanism activated in response to reduced energy availability (Rogers, 2014).

Genetic interventions that conserve mitochondrial energetic capacity have been shown to maintain a favorable redox state and regenerative tissue homeostasis. This is particularly beneficial in the fly midgut, which facilitates nutrient uptake, waste removal and response to bacterial infection. Indy mutant flies have striking increases in the steady-state expression of the GstE1 and GstD5 ROS detoxification genes. As a result, any increase in ROS levels, whether from mitochondrial demise or exposure to external ROS sources can be readily metabolized to prevent accumulation of oxidative damage. Such conditions not only promote oxidative stress resistance, but also preserve ISC homeostasis as demonstrated by consistent proliferation rates throughout Indy mutant lifespan and preserved intestinal architecture in aged Indy mutant midguts. Thus, enhanced ROS detoxification mechanisms induced by Indy reduction and subsequent elevation of dPGC-1 contributes to preservation of ISC functional efficiency, and may be a contributing factor to the long-lived phenotype of Indy mutant flies (Rogers, 2014).

Several lines of evidence indicate that INDY and dPGC-1 are part of the same regulatory network in the midgut, in which dPGC-1 functions as a downstream effector of INDY. The similarity between dPGC-1 mRNA levels and survivorship of flies overexpressing dPGC-1 in esg-positive cells and Indy mutant flies suggests that Indy and dPGC-1 interact to extend lifespan. This is further supported by the lack of additional longevity extension when dPGC-1 is overexpressed in esg-positive cells of Indy mutant flies. Moreover, hypomorphic dPGC-1 flies in an Indy mutant background are similar to controls with respect to life span, declines in mitochondrial activity and ROS-detoxification. Together, these data suggest that dPGC-1 must be present to mediate the downstream physiological benefits and lifespan extension of Indy mutant flies (Rogers, 2014).

There are some physiological differences between the effects of Indy mutation and dPGC-1 overexpression in esg-positive cells. While Indy mutant flies are less resistant to starvation and more resistant to paraquat, a recent report showed that overexpressing dPGC-1 in esg-positive cells has no effect on resistance to starvation or oxidative stress. Additionally, mice lacking skeletal muscle PGC-1α were found to lack mitochondrial changes associated with CR but still showed other CR-mediated metabolic changes. In the fly INDY is predominantly expressed in the midgut, fat body and oenocytes, though there is also low level expression in the malpighian tubules, salivary glands, antenae, heart and female follicle cell membranes. Thus, the effects of INDY on intermediary metabolism and longevity could be partially independent from dPGC-1 or related to changes in tissues other than the midgut (Rogers, 2014).

This study suggests that INDY may function as a physiological regulator of mitochondrial function and related metabolic pathways, by modulating nutrient flux in response to nutrient availability and energetic demands. Given the localization of INDY in metabolic tissues, and importance of regulated tissue homeostasis during aging, these studies highlight INDY as a potential target to improved health and longevity. Reduced Indy expression causes similar physiological changes in flies, worms and mice indicating its regulatory role would be conserved. Further work should examine the interplay between Indy mutation and metabolic pathways, such as insulin signaling, which have been shown to promote stem cell maintenance and healthy aging in flies and mice. In doing so, the molecular mechanisms, which underlie Indy mutant longevity may provide insight for anti-aging therapies (Rogers, 2014).

Intergenerational inheritance of high fat diet-induced cardiac lipotoxicity in Drosophila

Obesity is strongly correlated with lipotoxic cardiomyopathy, heart failure and thus mortality. The incidence of obesity has reached alarming proportions worldwide, and increasing evidence suggests that the parents' nutritional status may predispose their offspring to lipotoxic cardiomyopathy. However, to date, mechanisms underlying intergenerational heart disease risks have yet to be elucidated. This study reports that cardiac dysfunction induced by high-fat-diet (HFD) persists for two subsequent generations in Drosophila and is associated with reduced expression of two key metabolic regulators, adipose triglyceride lipase (ATGL/bmm) and transcriptional cofactor PGC-1. Evidence is provided that targeted expression of ATGL/bmm in the offspring of HFD-fed parents protects them, and the subsequent generation, from cardio-lipotoxicity. Furthermore, it was found that intergenerational inheritance of lipotoxic cardiomyopathy correlates with elevated systemic H3K27 trimethylation. Lowering H3K27 trimethylation genetically or pharmacologically in the offspring of HFD-fed parents prevents cardiac pathology. This suggests that metabolic homeostasis is epigenetically regulated across generations (Guida, 2019).

Several studies have established a critical role for triacylglyceride (TAG) hydrolysis in cardiac metabolism and function, in both healthy and diseased hearts. This study shows that acute HFD (5 days of food supplemented with 30% coconut oil) induces lipotoxic cardiomyopathy that can be inherited by the next two generations, via the parental germlines, even when the offspring are raised on normal food diet (NFD). Similar to what has been described by epidemiological studies on the offspring of obese pregnant women, this study found in the fly model that parental HFD led to first generation progeny with increased adult body weight and increased fat content in late-stage embryos. This was no longer the case in second generation offspring, and adult progeny did not exhibit an increase in fat content relative to body weight in either generations. In contrast, metabolic reprogramming across generations was particularly evident in the systemic reduction in the transcript levels of ATGL/bmm lipase and its downstream target PGC-1/spargel, a key regulator of energy metabolism. The intergenerational lipotoxic cardiomyopathy model was further validated by genetically reducing PGC-1 expression in the parents (PGC-1xp heterozygotes), which causes similar cardiac lipotoxicity as HFD exposure. This was sufficient to alter the +/+ offspring's metabolic state, leading to lipotoxic cardiomyopathy later in life, even though these flies carry two wild-type copies of PGC-1. Of note, the partial reduction of PGC-1 induced by acute and parental HFD in control flies and PGC-1XP heterozygous mutant flies is likely having a profound effect on mitochondrial biogenesis that could be underlying the observed heart dysfunction (Guida, 2019).

The experiments presented in this study indicate that HFD and reduced PGC-1 expression levels have the ability to modify the offspring's metabolism leading to heart dysfunction. Thus, it is speculated that parental HFD-dependent metabolic reprogramming and associated lipotoxic cardiomyopathy in the progeny could be prevented by increasing ATGL/bmm levels. Indeed, targeted transgenic expression of bmm is able to reset the altered metabolic state induced by parental HFD, and thus protects the progeny from cardiac lipotoxicity. Remarkably, induction of bmm expression in the early embryo is sufficient to render the adult progeny (G1), as well as the following generation (G2), resistant to acute HFD (Guida, 2019).

The presented data support the hypothesis that the quality of nutrition during gestation leads to fetal programming that functions as a key determinant in establishing predisposition and/or susceptibility to metabolic and cardiovascular disorders later in life. While this hypothesis is sustained by several epidemiological studies, including the Dutch Hunger Winter studies, and many animal models with different environmental stressors, the underling mechanisms on the intergenerational inheritance of lipotoxic cardiomyopathy induced by parental HFD remain mostly unknown. The Drosophila model in this study indicates that the inheritance of altered histone modifications is a key mechanism in the propagation of lipotoxic cardiomyopathy across generations (Guida, 2019).

Histone modifications are essential in regulating chromatin packaging and gene expression for proper development and cell function. In turn, metabolites serve as co-factors for chromatin modifying enzymes, allowing protein activity and gene expression to match the specific energy requirements. It was found that HFD, and potentially its maladaptive fluctuation in metabolites, can lead to changes in chromatin structure and gene expression that are transmitted to the next generation. Indeed, a major finding presented in this study is the involvement of the PRC2 complex in regulating metabolism and heart function in response to a HFD, via H3K27me3 gene repression across generations. The increase in H3K27me3 global levels in the adult flies upon acute or parental HFD supports the hypothesis that HFD causes changes in the epigenome that have lifelong consequences. The results are in line with previous findings in Caenorhabditis elegans and mice, which provide evidence that PRC2-mediated epigenetic modifications in the germ cells can be transmitted to embryos by sperm and/or oocytes. In addition, this study found that reduction of H3K27me3, either by overexpression of UTX or inhibition of EzH2, can prevent the deleterious effects of a parental HFD on heart function and metabolism. Of note, at this point it cannot be ruled out that UTX overexpression and EzH2 inhibition might also have H3K27me3-independent effects (Guida, 2019).

Overall, using the genetic model of Drosophila, this study provides first evidence that early embryonic and tissue-specific modulation of lipolysis in myocardial progenitors, adipose tissue, and the germline leads to tissue-specific and/or systemic metabolic reprogramming or pre-programming that persists into adulthood. Importantly, the imposed metabolic state appears to be inherited by the next two generations as either a predisposition to metabolic imbalance and cardiac dysfunction, or a protection from HFD insult when bmm is overexpressed. Moreover, this study provides evidence that metabolic re-programming that leads to fat accumulation and cardiac lipotoxicity correlates with overall levels of H3K27me3 epigenetic marks, which can be reversed by genetic or pharmacological reduction of H3K27me3 levels. The findings shed light on possible causes of obesogenic heritability and early adult onset of cardiovascular disease and diabetes, which appear to have their roots in the diet and overall metabolic state of the parents. Importantly, this study demonstrates that targeted genetic or pharmacological interventions in the progeny are able to counteract the detrimental effects on cardiac function of parental dietary insults, a protection that persists even in the subsequent generation against acute HFD. These findings provide new perspectives for tackling metabolic syndrome effects across generations and preventing lipotoxic cardiomyopathies (Guida, 2019).

Female-biased upregulation of insulin pathway activity mediates the sex difference in Drosophila body size plasticity

Nutrient-dependent body size plasticity differs between the sexes in most species, including mammals. Previous work in Drosophila showed that body size plasticity was higher in females, yet the mechanisms underlying increased female body size plasticity remain unclear. This study discovered that a protein-rich diet augments body size in females and not males because of a female-biased increase in activity of the conserved insulin/insulin-like growth factor signaling pathway (IIS). This sex-biased upregulation of IIS activity was triggered by a diet-induced increase in stunted mRNA in females, and required Drosophila insulin-like peptide 2, illuminating new sex-specific roles for these genes. Importantly, this study shows that sex determination gene transformer promotes the diet-induced increase in stunted mRNA via transcriptional coactivator Spargel to regulate the male-female difference in body size plasticity. Together, these findings provide vital insight into conserved mechanisms underlying the sex difference in nutrient-dependent body size plasticity (Millington, 2021).

In many animals, body size plasticity in response to environmental factors such as nutrition differs between the sexes. While past studies have identified mechanisms underlying nutrient-dependent growth in a mixed-sex population, and revealed factors that promote sex-specific growth in a single nutritional context, the mechanisms underlying the sex difference in nutrient-dependent body size plasticity remain unknown. This study showed that females have higher phenotypic plasticity compared with males when reared on a protein-rich diet, and elucidated the molecular mechanisms underlying the sex difference in nutrient-dependent body size plasticity in this context. The data suggests a model in which high levels of dietary protein augment female body size by stimulating an increase in IIS activity, where a requirement was identified for dilp2 and stunted (sun) in promoting this nutrient-dependent increase in IIS activity. Importantly, it was discovered that tra is the factor responsible for stimulating sun mRNA levels and IIS activity in a protein-rich context, revealing a novel role for sex determination gene tra in regulating phenotypic plasticity. Mechanistically, tra enhanced sun mRNA levels and body size in protein-rich conditions via transcriptional coactivator Srl, identifying Srl as one link between tra and the nutrient-dependent regulation of gene expression. Together, these findings provide new insight into how Drosophila females achieve increased nutrient-dependent body size plasticity compared with males (Millington, 2021).

One key feature of this increased phenotypic plasticity in females was a female-biased increase in IIS activity in a protein-rich context. This reveals a previously unrecognized sex difference in the coupling between IIS activity and dietary protein. In females, there was tight coupling between increased nutrient input and enhanced IIS activity across a wide protein concentration range in all control genotypes. In males, this close coordination between dietary protein and IIS activity was weaker in a protein-rich context. The data shows that sex-biased nutrient-dependent change to IIS activity during development is physiologically significant, as it supports an increased rate of growth and consequently larger body size in females but not in males raised on a protein-rich diet. In future studies, it will be important to determine whether the sex difference in coupling between nutrients and IIS activity exists in other contexts. For example, previous studies on the extension of life span by dietary restriction have shown that male and female flies differ in the concentration of nutrients that produces the maximum life span extension, and in the magnitude of life span extension produced by dietary restriction. Similar sex-specific effects of dietary restriction and reduced IIS on life span have also been observed in mice and humans. Future studies will be needed to determine whether a male-female difference in coupling between nutrients and IIS activity account for these sex-specific life span responses to dietary restriction. Indeed, given that sex differences have been reported in the risk of developing diseases associated with overnutrition and dysregulation of IIS activity such as obesity and type 2 diabetes, more detailed knowledge of the male-female difference in coupling between nutrients and IIS activity in other models may provide insights into this sex-biased risk of disease (Millington, 2021).

In addition to revealing a sex difference in the nutrient-dependent upregulation of IIS activity, the data identified a female-specific requirement for dilp2 and sun in mediating the diet-induced increase in IIS activity in a protein-rich context. While previous studies have shown that both dilp2 and sun positively regulate body size, this study describes new sex-specific roles for dilp2 and sun in nutrient-dependent phenotypic plasticity. Elegant studies have shown that sun is a secreted factor that stimulates Dilp2 release from the IPCs. Together with the current data, this suggests a model in which females are able to achieve a larger body size in a protein-rich diet because they have the ability to upregulate sun mRNA levels, whereas males do not. Indeed, this study shows that higher sun mRNA levels are sufficient to augment body size. This model aligns well with findings from two previous studies on Dilp2 secretion in male and female larvae. The first study, which raised larvae on a protein-rich diet equivalent to the 2Y diet (high protein), found increased Dilp2 secretion in females compared to males. The second study, which raised larvae on a diet equivalent to the 1Y diet (low protein), found no sex difference in Dilp2 secretion and no effects of dilp2 loss on body size. Thus, while these previous studies differed in their initial findings on a sex difference in Dilp2 secretion, the current data reconcile these minor differences by identifying context-dependent effects of dilp2 on body size. It is important to note that absolute confirmation of a sex difference in hemolymph Dilp2 levels will be needed in future studies because the body size plasticity defects in the dilp2-HF strain precluded its use as a tool to quantify circulating Dilp2 levels in this study. Future studies will also need to determine whether these sex-specific and context-dependent effects of dilp2 are observed in other phenotypes regulated by dilp2 and other dilp genes. For example, flies carrying mutations in dilp genes show changes to aging, metabolism, sleep, and immunity, among other phenotypes. Further, it will be interesting to determine whether the sex-specific regulation of sun is observed in any other contexts, and whether it will influence sex differences in phenotypes associated with altered IIS activity, such as life span (Millington, 2021).

While these findings on sun and dilp2 provide mechanistic insight into the molecular basis for the larger body size of females reared on a protein-rich diet, a key finding from this study was the identification of sex determination gene tra as the factor that confers plasticity to females. Normally, nutrient-dependent body size plasticity is higher in females than in males in a protein-rich context. In females lacking a functional Tra protein, however, this increased nutrient-dependent body size plasticity was abolished. In males, which normally lack a functional Tra protein, ectopic Tra expression conferred increased nutrient-dependent body size plasticity. While a previous study showed that on the 2Y diet Tra promotes Dilp2 secretion , the current study extends this finding in two ways: by identifying sun as one link between Tra, Dilp2, and changes to IIS activity; and by showing that Tra regulates sun mRNA via conserved transcriptional coactivator Srl. While previous studies discovered Srl as the factor that promotes sun mRNA levels in response to dietary protein in a mixed-sex larval population, the current findings reveal a previously unrecognized sex-specific role for Srl in regulating transcription. Because loss of Tra reduces Srl transcriptional activity, this new link between Tra and Srl suggests an additional way in which Tra may impact gene expression beyond its canonical downstream targets dsx and fru. While this builds on recent studies that reveal a number of additional Tra-regulated genes, it will be important to determine whether these additional Tra-regulated genes including sun represent direct targets of Tra/Srl. Future studies will also be needed to elucidate how Tra impacts Srl transcriptional activity in a context-dependent manner. However, uncovering a connection between a sex determination gene and a key regulator of genes involved in mitochondrial function suggests an additional mechanism that may contribute to sex differences in phenotypes affected by mitochondrial function (e.g., lifespan). In addition, it will be critical to explore how the presence of Tra allows an individual to couple dietary protein with body size. Because the tra locus is regulated both by alternative splicing and transcription, and Tra protein is regulated by phosphorylation, this study highlights the importance of additional studies on the regulation of the tra genomic locus and Tra protein throughout development to gain mechanistic insight into its effects on nutrient-dependent body size plasticity (Millington, 2021).

While the main outcome of this work was to reveal the molecular mechanisms that regulate the sex difference in nutrient-dependent body size plasticity, this study also provides some insight into how genes that contribute to nutrient-dependent body size plasticity affect female fecundity and male fertility. The findings align well with previous studies demonstrating that increased nutrient availability during development and a larger female body size confers increased ovariole number and fertility, as females lacking either dilp2 or fat body-derived sun were unable to augment egg production in a protein-rich context. Given that previous studies demonstrate IIS activity influences germline stem cells in the ovary in adult flies, there is a clear reproductive benefit that arises from the tight coupling between nutrient availability, IIS activity, and body size in females. In males, however, the relationship between fertility and body size remains less clear. While larger males are more reproductively successful both in the wild and in laboratory conditions. Given that this study revealed no significant increase in the number of progeny produced by larger males, the fertility benefits that accompany a larger body size in males may be context-dependent. For example, a larger body size increases the ability of males to outcompete smaller males. Thus, in crowded situations, a bigger body may provide significant fertility gains. However, in conditions where nutrients are limiting, an imbalance in the allocation of energy from food to growth rather than to reproduction may decrease fertility. Future studies will need to resolve the relationship between body size and fertility in males, as this will suggest the ultimate reason(s) for the sex difference in nutrient-dependent body size plasticity (Millington, 2021).

High-resolution dynamics of the transcriptional response to nutrition in Drosophila: a key role for dFOXO

A high-resolution time series of transcript abundance was generated to describe global expression dynamics in response to nutrition in Drosophila. Nonparametric change-point statistics revealed that within 7 h of feeding upon yeast, transcript levels changed significantly for approximately 3,500 genes or 20% of the Drosophila genome. Differences as small as 15% were highly significant, and 80% of the changes were <1.5-fold. Notably, transcript changes reflected rapid downregulation of the nutrient-sensing insulin and target of rapamycin pathways, shifting of fuel metabolism from lipid to glucose oxidation, and increased purine synthesis, TCA-biosynthetic functions and mitochondria biogenesis. To investigate how nutrition coordinates these transcriptional changes, feeding-induced expression changes were compared with those induced by the insulin-regulated transcription factor dFOXO in Drosophila S2 cells. Remarkably, 28% (995) of the nutrient-responsive genes were regulated by activated dFOXO, including genes of mitochondrial biogenesis and a novel homolog of mammalian peroxisome proliferator-gamma coactivator-1 (PGC-1), a transcriptional coactivator implicated in controlling mitochondrial gene expression in mammals. These data implicate dFOXO as a major coordinator of the transcriptional response to nutrients downstream of insulin and suggest that mitochondria biogenesis is linked to insulin signaling via dFOXO-mediated repression of a PGC-1 homolog (Gershman, 2007).

Given the change in mRNA encoding proteins involved in intermediary metabolism upon refeeding, transcriptional changes were expected in genes underlying mitochondrial function. Indeed, many genes whose products directly participate in mitochondrial substrate transport and ATP synthesis were coordinately upregulated. These included at least 13 genes encoding proteins with functions in electron transport and thirteen substrate carriers. Indeed, of 232 genes assigned Gene Ontology (GO) functions associated with mitochondria, 54% changed with refeeding, and 91% of these were increased (Gershman, 2007).

Most strikingly, there was a marked and rapid increase in transcripts encoding genes with roles in mitochondrial biogenesis, such as membrane preprotein translocases, chaperones, mitochondrial DNA binding proteins, and nuclear encoded mitochondrial ribosome proteins. Of 60 nuclear encoded mitochondrial ribosomal genes on the array, expression of 54 was increased an average of 44% at 5-7 h after refeeding. The induction of mitochondrial ribosomal proteins contrasts with the relative stasis of transcripts encoding proteins of the cytoplasmic ribosome. Of the 39 cytoplasmic ribosome genes represented on the array, mRNA for seven were moderately increased and two were reduced. An expansion of mitochondria within cells may reflect de novo adipogenesis in adult fat body when females first feed on yeast, similar to what is observed in mammalian 3T3-L1 cells that increase mitochondrial density as they differentiate into adipocytes. The observed increase in mitochondrial gene expression may also reflect activity in skeletal muscle cells, given that nutrients have been shown to regulate expression of mitochondrial oxidative phosphorylation genes in mammalian muscle (Gershman, 2007).

How nutrients regulate mitochondrial capacity is poorly understood. Many nutrient-induced transcripts encoding proteins of mitochondria biogenesis were broadly repressed in cells expressing dFOXO-A3. Of the 54 mRNAs for mitochondrial ribosome proteins that increased upon refeeding, 42 were downregulated by dFOXO-A3. Likewise, of the 25 upregulated genes with functions in mitochondrial biogenesis, 14 were repressed in dFOXO-A3 cells. In contrast, only six of the 53 nutrient-regulated, nuclear-encoded genes for mitochondrial function were inversely regulated by dFOXO-A3. Therefore, insulin, presumably via dFOXO, has a strong and selective impact on genes associated with mitochondrial biogenesis (Gershman, 2007).

One candidate to mediate mitochondrial biogenesis is PGC-1. PGC-1α of mammals stimulates mitochondrial biogenesis in muscle, brown adipose tissue, and adipogenic 3T3-L1 cells. Interestingly, a mRNA of the single ortholog of a PGC-like peptide in D. melanogaster (CG9809, Spargel) increases upon refeeding, and declines in dFOXO-A3 cells. CG9809 encodes a predicted protein of 1,088 amino acids that exhibits 68 or 52% homology with mammalian PGC-1α or PGC-1ß, respectively, in their COOH-terminal RNA-binding motif. Other domains in common with its mammalian homologs include an arginine-serine-rich domain located NH2-terminal to the RNA-binding motif, an acidic NH2-terminal domain and leucine-rich motifs, although the canonical LXXLL nuclear receptor binding motif is not present. However, the LXXLL motif is not absolutely required for coactivator binding, and CG9809 does contain a variant of this motif near its COOH terminus, FXXLL, which has been reported to function in nuclear receptor binding. Notably, this sequence is conserved in all mammalian PGC-1 family members. Beside a parallel based on sequence, orthologous targets of PGC-1 were elevated in refed flies and were reduced by dFOXO-A3 in S2 cells, including mitochondrial transcription factor A. Consistent with these data, insulin has been reported to upregulate PGC-1α and PGC-1ß mRNA levels in human muscle, although the mechanism was unclear. These data suggest that insulin signaling may be a conserved regulator of normal mitochondrial biogenesis via FOXO-mediated control of PGC-1-like cofactors. Importantly, this suggests a mechanistic basis for the prevalent mitochondrial dysfunction in humans with insulin resistance and diabetes (Gershman, 2007).


Search PubMed for articles about Drosophila Spargel

Andersson, U. and Scarpulla, R. C. (2001). Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells. Mol. Cell. Biol. 21: 3738-3749. PubMed ID: 11340167

Baltzer, C., Tiefenbock, S. K., Marti, M. and Frei, C. (2009). Nutrition controls mitochondrial biogenesis in the Drosophila adipose tissue through Delg and cyclin D/Cdk4. PLoS One 4: e6935. PubMed ID: 19742324

Choi, C. S., et al. (2008). Paradoxical effects of increased expression of PGC-1alpha on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism. Proc. Natl. Acad. Sci. 105: 19926-19931. PubMed ID: 19066218

Cunningham, J. T., et al. (2007). mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 450: 736-740. PubMed ID: 18046414

Gershman, B., et al. (2007). High-resolution dynamics of the transcriptional response to nutrition in Drosophila: a key role for dFOXO. Physiol. Genomics 29: 24-34. PubMed ID: 17090700

Gleyzer, N., Vercauteren, K. and Scarpulla, R. C. (2005). Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol. Cell. Biol. 25: 1354-1366. PubMed ID: 15684387

Guida, M. C., Birse, R. T., Dall'Agnese, A., Toto, P. C., Diop, S. B., Mai, A., Adams, P. D., Puri, P. L. and Bodmer, R. (2019). Intergenerational inheritance of high fat diet-induced cardiac lipotoxicity in Drosophila. Nat Commun 10(1): 193. PubMed ID: 30643137

Kamei, Y., et al. (2003). PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc. Natl. Acad. Sci. 100: 12378-12383. PubMed ID: 14530391

Koo, S. H., et al. (2004). PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3. Nat. Med. 10: 530-534. PubMed ID: 15107844

Lai, L., et al. (2008). Transcriptional coactivators PGC-1alpha and PGC-lbeta control overlapping programs required for perinatal maturation of the heart. Genes Dev. 22: 1948-1961. PubMed ID: 18628400

Lelliott, C. J., et al. (2006). Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLoS Biol. 4: e369. PubMed ID: 17090215

Leone, T. C., et al. (2005). PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 3: e101. PubMed ID: 15760270

Lin, J., Handschin, C. and Spiegelman, B. M. (2005). Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1: 361-370. PubMed ID: 16054085

Millington, J. W., Brownrigg, G. P., Chao, C., Sun, Z., Basner-Collins, P. J., Wat, L. W., Hudry, B., Miguel-Aliaga, I. and Rideout, E. J. (2021). Female-biased upregulation of insulin pathway activity mediates the sex difference in Drosophila body size plasticity. Elife 10. PubMed ID: 33448263

Mootha, V. K., et al. (2004). Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc. Natl. Acad. Sci. 101: 6570-6575. PubMed ID: 15100410

Pagel-Langenickel, I., et al. (2008). PGC-1alpha integrates insulin signaling, mitochondrial regulation, and bioenergetic function in skeletal muscle. J. Biol. Chem. 283: 22464-22472. PubMed ID: 18579525

Puigserver, P., et al. (1998). A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92: 829-839. PubMed ID: 9529258

Puigserver, P. and Spiegelman, B. M. (2003). Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr. Rev. 24: 78-90. PubMed ID: 12588810

Rogers, R.P. and Rogina, B. (2014). Increased mitochondrial biogenesis preserves intestinal stem cell homeostasis and contributes to longevity in Indy mutant flies. Aging (Albany NY). 6: 335-350. 24827528

Scarpulla, R. C. (2008). Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol. Rev. 88: 611-638. PubMed ID: 18391175

Schreiber, S. N., et al. (2004). The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis. Proc. Natl. Acad. Sci. 101: 6472-6477. PubMed ID: 15087503

Sonoda, J., et al. (2007). PGC-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. Proc. Natl. Acad. Sci. 104: 5223-5228. PubMed ID: 17360356

Teleman, A. A., Hietakangas, V., Sayadian, A. C. and Cohen, S. M. (2008). Nutritional control of protein biosynthetic capacity by insulin via Myc in Drosophila. Cell. Metab. 7: 21-32. PubMed ID: 18177722

Tiefenböck, S. K., Baltzer, C., Egli, N. A. and Frei, C. (2010). The Drosophila PGC-1 homologue Spargel coordinates mitochondrial activity to insulin signalling. EMBO J. 29(1): 171-83. PubMed ID: 19910925

Uldry, M., et al. (2006). Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell. Metab. 3: 333-341. PubMed ID: 16679291

Vercauteren, K., Gleyzer, N. and Scarpulla, R. C. (2008). PGC-1-related coactivator complexes with HCF-1 and NRF-2beta in mediating NRF-2(GABP)-dependent respiratory gene expression. J. Biol. Chem. 283: 12102-12111. PubMed ID: 18343819

Vianna, C. R., et al. (2006). Hypomorphic mutation of PGC-1beta causes mitochondrial dysfunction and liver insulin resistance. Cell. Metab. 4: 453-464. PubMed ID: 17141629

Wu, Z., et al. (1999). Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98: 115-124. PubMed ID: 10412986

Biological Overview

date revised: 18 February 2024

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