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Mitochondrial regulator PGC-1a-Modulating the modulator.

ABSTRACT: Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a) is a central regulator of metabolism that is poised at the intersection of myriad intracellular signaling pathways. In this brief update, we discuss regulation of PGC-1a at multiple levels, including transcriptional, post-transcriptional, and post-translational modifications. We discuss recently identified small molecule effectors of PGC-1a that offer translational potential and promise new insight into PGC-1a biology. We highlight novel mechanistic insights relating to PGC-1a's interactions with RNA to enhance transcription and potentially influence transcript processing. Finally, we place these exciting new data in the context of aging biology, offering PGC-1a as a candidate target with terrific potential in anti-aging interventions.

SUBMITTER: Miller KN

PROVIDER: S-EPMC6690794 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Mitochondrial regulator PGC-1a-Modulating the modulator.

Miller Karl N KN Clark Josef P JP Anderson Rozalyn M RM

Current opinion in endocrine and metabolic research 20190227

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a) is a central regulator of metabolism that is poised at the intersection of myriad intracellular signaling pathways. In this brief update, we discuss regulation of PGC-1a at multiple levels, including transcriptional, post-transcriptional, and post-translational modifications. We discuss recently identified small molecule effectors of PGC-1a that offer translational potential and promise new insight into PGC-1a biology. ...[more]

PMID: 31406949

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Skeletal muscle PGC-1a mediates mitochondrial, but not metabolic, changes during calorie restriction.

Project description:Calorie restriction (CR) is a dietary intervention that extends lifespan and healthspan in a variety of organisms. CR improves mitochondrial energy production, fuel oxidation and reactive oxygen species scavenging in skeletal muscle and other tissues, and these processes are thought to be critical to the benefits of CR. PGC-1a is a transcriptional coactivator that regulates mitochondrial function and is induced by CR. Consequently, many of the mitochondrial and metabolic benefits of CR are attributed to increased PGC-1a activity. To test this model for the first time, we examined the metabolic and mitochondrial response to CR in mice lacking skeletal muscle PGC-1a (MKO). Surprisingly, MKO mice demonstrated a normal improvement in glucose homeostasis in response to CR, indicating that skeletal muscle PGC-1a is dispensable for the whole-body benefits of CR. In contrast, gene expression profiling and electron microscopy demonstrated that PGC-1a is required for the full CR-induced increases in mitochondrial gene expression and mitochondrial density in skeletal muscle. These results demonstrate that PGC-1a is a major regulator of the mitochondrial response to CR in skeletal muscle, but surprisingly show that neither PGC-1a nor mitochondrial biogenesis in skeletal muscle are required for the metabolic benefits of CR. Control (FLOX) and PGC-1a skeletal muscle specific knock out (MKO) mice were placed on a control diet [C] or a calorie restriction diet [CR] for 12 weeks. RNA was isolated from TA/EDL muscles for microarray analysis. The following numbers of mice were analyzed from each group: C FLOX: n = 6; C MKO: n = 7; CR FLOX: n = 6; CR MKO: n = 7. Mice were mixed C57/BL6 and 129 background.

2012-02-04 | E-GEOD-34773 | biostudies-arrayexpress

PGC-1a isoform-specific nuclear interactome

Project description:PGC-1α (Peroxisome proliferator-activated receptor gamma coactivator-1alpha) coactivators regulate adaptive gene expression in response to challenges such as cold exposure, fasting, or physical exercise to balance energy supply and demand. Transcription of a single PGC-1α gene produces different isoforms (e.g. PGC-1α1 to α4) with different biological functions. We aimed to characterize the nuclear interactome for each PGC-1α variant, in particular the transcription factors they bind to regulate gene expression. This was done by generating GST-fusions of all PGC-1a variants, expressed in an insect cell system. These were used to capture associated protein complexes from HeLa nuclear extracts.

2022-03-01 | PXD009232 | Pride

Skeletal muscle PGC-1a mediates mitochondrial, but not metabolic, changes during calorie restriction.

2012-02-04 | GSE34773 | GEO

PGC-1a overexpression in SH-SY5Y cells

Project description:SH-SY5Y cells were transfected with either GFP control or PGC-1a overexpression adenovirus and RNA was isolated after 48 hours and sequenced in order to understand what genes are differentially expressed with the presence of PGC-1a in neuron like cells. This experiment shows that genes related to neuron health and mitochondiral function are controlled by PGC-1a. We also analyze the promoter of upregualted genes found here to figure out potential partners that co-regulate with PGC-1a.

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Control of secreted protein gene expression and the mammalian secretome by the metabolic regulator PGC-1a

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PGC-1{alpha} and PGC-1{beta} regulate mitochondrial density in neurons.

Project description:Recent studies indicate that regulation of cellular oxidative capacity through enhancing mitochondrial biogenesis may be beneficial for neuronal recovery and survival in human neurodegenerative disorders. The peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) has been shown to be a master regulator of mitochondrial biogenesis and cellular energy metabolism in muscle and liver. The aim of our study was to establish whether PGC-1alpha and PGC-1beta control mitochondrial density also in neurons and if these coactivators could be up-regulated by deacetylation. The results demonstrate that PGC-1alpha and PGC-1beta control mitochondrial capacity in an additive and independent manner. This effect was observed in all studied subtypes of neurons, in cortical, midbrain, and cerebellar granule neurons. We also observed that endogenous neuronal PGC-1alpha but not PGC-1beta could be activated through its repressor domain by suppressing it. Results demonstrate also that overexpression of SIRT1 deacetylase or suppression of GCN5 acetyltransferase activates transcriptional activity of PGC-1alpha in neurons and increases mitochondrial density. These effects were mediated exclusively via PGC-1alpha, since overexpression of SIRT1 or suppression of GCN5 was ineffective where PGC-1alpha was suppressed by short hairpin RNA. Moreover, the results demonstrate that overexpression of PGC-1beta or PGC-1alpha or activation of the latter by SIRT1 protected neurons from mutant alpha-synuclein- or mutant huntingtin-induced mitochondrial loss. These evidences demonstrate that activation or overexpression of the PGC-1 family of coactivators could be used to compensate for neuronal mitochondrial loss and suggest that therapeutic agents activating PGC-1 would be valuable for treating neurodegenerative diseases in which mitochondrial dysfunction and oxidative damage play an important pathogenic role.

| S-EPMC2755862 | biostudies-other

Transcription profiling of striata from PGC-1a knockout mice and litter mate controls to understand the roles of PGC-1a.

Project description:Huntington's Disease (HD) is an inherited neurodegenerative disease caused by a glutamine repeat expansion in huntingtin protein. Transcriptional deregulation and altered energy metabolism have been implicated in HD pathogenesis. We report here that mutant huntingtin causes disruption of mitochondrial function by inhibiting expression of PGC-1a, a transcriptional coactivator that regulates several metabolic processes including mitochondrial biogenesis and respiration. Mutant huntingtin represses PGC-1a gene transcription by associating with the promoter and interfering with the CREB/TAF4-dependent transcriptional pathway critical for the regulation of PGC-1a gene expression. Crossbreeding of PGC-1a knockout mice with HD knock-in mice leads to increased neurodegeneration of striatal neurons and motor abnormalities in the HD mice. Importantly, expression of PGC-1a partially reverses the toxic effects of mutant huntingtin in cultured striatal neurons. Moreover, lentiviral-mediated delivery of PGC-1a in the striatum provides neuroprotection in the transgenic HD mice. These studies suggest a key role for PGC-1a in the control of energy metabolism in the early stages of HD pathogenesis. Experiment Overall Design: Total RNA was extracted from striata of 3 pgc1 KO mice and 3 littermate controls using the RNeasy Mini Kit (Qiagen) according to manufacturer's protocol. Samples were analyzed using RNA 6000 Nano LabChip kit on a 2100 Bioanalyzer (Agilent Technologies) to ensure integrity of RNA.

2007-11-13 | E-GEOD-5786 | biostudies-arrayexpress

PGC-1a integrates a metabolism and growth network linked to caloric restriction.

Project description:Deleterious changes in energy metabolism have been linked to aging and disease vulnerability, while activation of mitochondrial pathways has been linked to delayed aging by caloric restriction (CR). The basis for these associations is poorly understood, and the scope of impact of mitochondrial activation on cellular function has yet to be defined. Here, we show that mitochondrial regulator PGC-1a is induced by CR in multiple tissues, and at the cellular level, CR-like activation of PGC-1a impacts a network that integrates mitochondrial status with metabolism and growth parameters. Transcriptional profiling reveals that diverse functions, including immune pathways, growth, structure, and macromolecule homeostasis, are responsive to PGC-1a. Mechanistically, these changes in gene expression were linked to chromatin remodeling and RNA processing. Metabolic changes implicated in the transcriptional data were confirmed functionally including shifts in NAD metabolism, lipid metabolism, and membrane lipid composition. Delayed cellular proliferation, altered cytoskeleton, and attenuated growth signaling through post-transcriptional and post-translational mechanisms were also identified as outcomes of PGC-1a-directed mitochondrial activation. Furthermore, in vivo in tissues from a genetically heterogeneous mouse population, endogenous PGC-1a expression was correlated with this same metabolism and growth network. These data show that small changes in metabolism have broad consequences that arguably would profoundly alter cell function. We suggest that this PGC-1a sensitive network may be the basis for the association between mitochondrial function and aging where small deficiencies precipitate loss of function across a spectrum of cellular activities.

| S-EPMC6718593 | biostudies-literature

Gene Expression Profiling of PGC-1a KO mouse striata

Project description:Huntington’s Disease (HD) is an inherited neurodegenerative disease caused by a glutamine repeat expansion in huntingtin protein. Transcriptional deregulation and altered energy metabolism have been implicated in HD pathogenesis. We report here that mutant huntingtin causes disruption of mitochondrial function by inhibiting expression of PGC-1a, a transcriptional coactivator that regulates several metabolic processes including mitochondrial biogenesis and respiration. Mutant huntingtin represses PGC-1a gene transcription by associating with the promoter and interfering with the CREB/TAF4-dependent transcriptional pathway critical for the regulation of PGC-1a gene expression. Crossbreeding of PGC-1a knockout mice with HD knock-in mice leads to increased neurodegeneration of striatal neurons and motor abnormalities in the HD mice. Importantly, expression of PGC-1a partially reverses the toxic effects of mutant huntingtin in cultured striatal neurons. Moreover, lentiviral-mediated delivery of PGC-1a in the striatum provides neuroprotection in the transgenic HD mice. These studies suggest a key role for PGC-1a in the control of energy metabolism in the early stages of HD pathogenesis. Keywords: PGC-1a, striatum

2006-10-05 | GSE5786 | GEO

Caloric restriction increases the resistance of aged heart to myocardial ischemia/reperfusion injury via modulating AMPK-SIRT<sub>1</sub>-PGC<sub>1a</sub> energy metabolism pathway.

Project description:A large number of data suggest that caloric restriction (CR) has a protective effect on myocardial ischemia/reperfusion injury (I/R) in the elderly. However, the mechanism is still unclear. In this study, we created the I/R model in vivo by ligating the mice left coronary artery for 45 min followed by reperfusion. C57BL/6J wild-type mice were randomly divided into a young group fed ad libitum (y-AL), aged fed ad libitum (a-AL) and aged calorie restriction group (a-CR, 70% diet restriction), and fed for 6 weeks. The area of myocardial infarction was measured by Evan's blue-TTC staining, plasma cholesterol content quantified by ELISA, fatty acids and glucose measured by Langendorff working system, as well as protein expression of AMPK/SIRT1/PGC1a signaling pathway related factors in myocardial tissue detected by immunoblotting. Our results showed that CR significantly reduced infarct size in elderly mice after I/R injury, promoted glycolysis regardless of I/R injury, and restored myocardial glucose uptake in elderly mice. Compared with a-AL group, CR significantly promoted the expression of p-AMPK, SIRT1, p-PGC1a, and SOD2, but decreased PPARγ expression in aged mice. In conclusion, our results suggest that CR protects elderly mice from I/R injury by altering myocardial substrate energy metabolism via the AMPK/SIRT1/PGC1a pathway.

| S-EPMC9899227 | biostudies-literature

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