The Drosophila PGC-1 homologue Spargel coordinates mitochondrial activity to insulin signalling

Tiefenböck, Stefanie K.; Baltzer, Claudia; Egli, Nicole; Frei, C.

doi:10.1038/emboj.2009.330

Cited by 105 publications

(134 citation statements)

References 60 publications

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“…In Drosophila, the PGC-1 homologue spargel is essential for mitochondrial gene expression and spargel mutants display respiration defects [76]. This fundamental role of PGC-1 coactivators in cellular respiration is conserved across species, redundant between all 3 family members and important in all tissues that express PGC-1 coactivators.…”

Section: Role Of Pgc-1 Coactivators In Oxidative Metabolism and Skelementioning

confidence: 99%

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

Eisele

Handschin

2013

Semin Immunopathol

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(150 -250 words) [165] Skeletal muscle is an organ involved in whole body movement and energy metabolism with the ability to dynamically adapt to different states of (dis-)use. At a molecular level, the peroxisome proliferatoractivated receptor  coactivators 1 (PGC-1) are important mediators of oxidative metabolism in skeletal muscle and in other organs. Musculoskeletal disorders as well as obesity and its sequelae are associated with PGC-1 dysregulation in muscle with a concomitant local or systemic inflammatory reaction. In this review, we outline the function of PGC-1 coactivators in physiological and pathological conditions as well as the complex interplay of metabolic dysregulation and inflammation in obesity with special focus on skeletal muscle. We further put forward the hypothesis that in this tissue, oxidative metabolism and inflammatory processes mutually antagonize each other. The nuclear factor κB (NF-B) pathway thereby plays a key role in linking metabolic and inflammatory programs in muscle cells. We conclude this review with a perspective about the consequences of such a negative crosstalk on the immune system and the possibilities this opens for clinical applications.

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Section: Role Of Pgc-1 Coactivators In Oxidative Metabolism and Skelementioning

confidence: 99%

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

Eisele

Handschin

2013

Semin Immunopathol

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“…These studies indicate that PGC-1a and PGC-1b are partially functionally complementary. Intriguingly, the Drosophila PGC-1 family homologue, Spargel, regulates mitochondrial mass, and in the larval fat body, Spargel mediates mitochondrial activity, cell growth, and transcription of target genes in response to insulin signaling (Tiefenbock et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Peri‐implantation lethality in mice lacking the PGC‐1‐related coactivator protein

Sun

Feng

et al. 2012

Developmental Dynamics

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Background: Members of the PPARg coactivator-1 (PGC-1) family are central transcriptional coactivators that regulate cell metabolic processes ranging from mitochondrial biogenesis to oxidative respiration. PGC-1-related coactivator (PPRC1 or PRC), initially identified as a member of the PGC-1 family, is believed to regulate mitochondria biogenesis, respiration pathways, and cell proliferation. However, its physiological role is not clearly understood. Here, we investigate the biological functions of PPRC1 in vivo using PPRC1 deficient mice generated by gene targeting. Results: Homozygous deficient PPRC1 mice failed to form egg cylinders and died after implantation but before embryonic day 6.5, whereas mice heterozygous for PPRC1 were viable, fertile and indistinguishable from their wild-type littermates. Furthermore, PPRC1 mRNA was expressed at the embryonic stage before implantation and was rapidly upregulated during the first day of embryoid body formation. The PPRC1 mRNA was then subsequently down-regulated, although its precise function at this stage of development was unclear. Conclusions: This is the first study to suggest a nonredundant role for PPRC1 in mouse early embryonic development. Developmental Dynamics 241:975-983, 2012. V C 2012 Wiley Periodicals, Inc.Key words: embryonic lethality; gene targeting; PGC-1-related coactivator; PGC-1 family Key findings:Disruption of pprc1 gene causes peri-implantation embryonic lethality. Developmental deficiencies in pprc1 2/2 embryos occur during peri-implantation. In vitro culturing of pprc1 2/2 blastocysts is susceptible to growth retardation. PPRC1 mRNA is expressed during preimplantation embryonic development. PPRC1 mRNA is rapidly up-regulated during early embryoid body formation. Accepted 23 February 2012Developmental Dynamics ABBREVIATIONS PGC-1 PPARg coactivator-1 PPRC1 PGC-1-a-related coactivator protein BAT brown adipose tissue ICM inner cell mass TG trophoblast giant cells E3.5 embryonic day 3.5 ESC embryonic stem cell EB embryoid body

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“…3H) and complex II (Fig. 3I) coactivator (PGC)-1 family of transcriptional coactivators are key regulators of mitochondrial activity in mammals (47) and Drosophila (48,49). Hence, we examined the expression of dPGC-1 in long-lived Parkin flies and controls.…”

Section: Parkin Overexpression Modulates Mitochondrial Dynamics and Amentioning

confidence: 99%

Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan

Rana

Rera

Walker

2013

Proc. Natl. Acad. Sci. U.S.A.

286

222

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Aberrant protein aggregation and mitochondrial dysfunction have each been linked to aging and a number of age-onset neurodegenerative disorders, including Parkinson disease. Loss-of-function mutations in parkin, an E3 ubiquitin ligase that functions to promote the ubiquitin-proteasome system of protein degradation and also in mitochondrial quality control, have been implicated in heritable forms of Parkinson disease. The question of whether parkin can modulate aging or positively impact longevity, however, has not been addressed. Here, we show that ubiquitous or neuron-specific up-regulation of Parkin, in adult Drosophila melanogaster, increases both mean and maximum lifespan without reducing reproductive output, physical activity, or food intake. Longlived Parkin-overexpressing flies display an increase in K48-linked polyubiquitin and reduced levels of protein aggregation during aging. Recent evidence suggests that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. However, the relationships between parkin gene activity, mitochondrial dynamics, and aging have not been explored. We show that the mitochondrial fusionpromoting factor Drosophila Mitofusin, a Parkin substrate, increases in abundance during aging. Parkin overexpression results in reduced Drosophila Mitofusin levels in aging flies, with concomitant changes in mitochondrial morphology and an increase in mitochondrial activity. Together, these findings reveal roles for Parkin in modulating organismal aging and provide insight into the molecular mechanisms linking aging to neurodegeneration.energy metabolism | healthspan | mitophagy | neuronal aging | proteostasis A dvanced age is a major risk factor for many neurodegenerative disorders, including both Alzheimer's disease and Parkinson disease (PD), and yet the molecular mechanisms that link aging and neurodegeneration are poorly understood. To understand this connection, it is necessary to identify the molecular events and pathways that integrate aging and neurodegenerative disease. Several lines of evidence suggest that a decline in the ability to prevent and eliminate protein misfolding (1) and impaired mitochondrial function (2) are important factors in the increased risk of disease and death associated with aging. More specifically, although the correlation between neurodegenerative disease and protein aggregation in the brain has long been recognized (3), recent work in the nematode Caenorhabditis elegans (4-6) and the fruit fly Drosophila melanogaster (7) has shown that aging per se is associated with increased aggregation of a large number of proteins. At the same time, a decline in mitochondrial gene expression and/or energetic capacity is a hallmark of aging across diverse species (2, 8), whereas a failure to eliminate dysfunctional mitochondria has been implicated in the pathophysiology of a number of neurodegenerative diseases, including PD (9).The ubiquitin-proteasome system (UPS) is a critical component of the cellular pro...

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The Drosophila PGC-1 homologue Spargel coordinates mitochondrial activity to insulin signalling

Cited by 105 publications

References 60 publications

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

Peri‐implantation lethality in mice lacking the PGC‐1‐related coactivator protein

Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan

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