Mitochondrial Regulator PGC-1a-Modulating the Modulator

Overview

Journal Curr Opin Endocr Metab Res

Specialty Endocrinology

Date 2019 Aug 14

PMID 31406949

Citations 33

Authors

Karl N Miller

Josef P Clark

Rozalyn M Anderson

Affiliations

Soon will be listed here.

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.

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References

Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V . Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 1999; 98(1):115-24. DOI: 10.1016/S0092-8674(00)80611-X. View

Puigserver P, Adelmant G, Wu Z, Fan M, Xu J, OMalley B . Activation of PPARgamma coactivator-1 through transcription factor docking. Science. 1999; 286(5443):1368-71. DOI: 10.1126/science.286.5443.1368. View

Yoon J, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J . Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature. 2001; 413(6852):131-8. DOI: 10.1038/35093050. View

Puigserver P, Rhee J, Lin J, Wu Z, Yoon J, Zhang C . Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. Mol Cell. 2001; 8(5):971-82. DOI: 10.1016/s1097-2765(01)00390-2. View

Lin J, Wu H, Tarr P, Zhang C, Wu Z, Boss O . Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature. 2002; 418(6899):797-801. DOI: 10.1038/nature00904. View

Puigserver P, Rhee J, Donovan J, Walkey C, Yoon J, Oriente F . Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature. 2003; 423(6939):550-5. DOI: 10.1038/nature01667. View

Wallberg A, Yamamura S, Malik S, Spiegelman B, Roeder R . Coordination of p300-mediated chromatin remodeling and TRAP/mediator function through coactivator PGC-1alpha. Mol Cell. 2003; 12(5):1137-49. DOI: 10.1016/s1097-2765(03)00391-5. View

Mootha V, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S . Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci U S A. 2004; 101(17):6570-5. PMC: 404086. DOI: 10.1073/pnas.0401401101. View

Nemoto S, Fergusson M, Finkel T . SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J Biol Chem. 2005; 280(16):16456-60. DOI: 10.1074/jbc.M501485200. View

10.

Rodgers J, Lerin C, Haas W, Gygi S, Spiegelman B, Puigserver P . Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005; 434(7029):113-8. DOI: 10.1038/nature03354. View

11.

Lerin C, Rodgers J, E Kalume D, Kim S, Pandey A, Puigserver P . GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha. Cell Metab. 2006; 3(6):429-38. DOI: 10.1016/j.cmet.2006.04.013. View

12.

Li X, Monks B, Ge Q, Birnbaum M . Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature. 2007; 447(7147):1012-6. DOI: 10.1038/nature05861. View

13.

Jager S, Handschin C, St-Pierre J, Spiegelman B . AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A. 2007; 104(29):12017-22. PMC: 1924552. DOI: 10.1073/pnas.0705070104. View

14.

Sano M, Tokudome S, Shimizu N, Yoshikawa N, Ogawa C, Shirakawa K . Intramolecular control of protein stability, subnuclear compartmentalization, and coactivator function of peroxisome proliferator-activated receptor gamma coactivator 1alpha. J Biol Chem. 2007; 282(35):25970-80. DOI: 10.1074/jbc.M703634200. View

15.

Anderson R, Barger J, Edwards M, Braun K, OConnor C, Prolla T . Dynamic regulation of PGC-1alpha localization and turnover implicates mitochondrial adaptation in calorie restriction and the stress response. Aging Cell. 2007; 7(1):101-11. PMC: 2253697. DOI: 10.1111/j.1474-9726.2007.00357.x. View

16.

Rodgers J, Lerin C, Gerhart-Hines Z, Puigserver P . Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Lett. 2007; 582(1):46-53. PMC: 2275806. DOI: 10.1016/j.febslet.2007.11.034. View

17.

Cunningham J, Rodgers J, Arlow D, Vazquez F, Mootha V, Puigserver P . mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007; 450(7170):736-40. DOI: 10.1038/nature06322. View

18.

Olson B, Hock M, Ekholm-Reed S, Wohlschlegel J, Dev K, Kralli A . SCFCdc4 acts antagonistically to the PGC-1alpha transcriptional coactivator by targeting it for ubiquitin-mediated proteolysis. Genes Dev. 2008; 22(2):252-64. PMC: 2192758. DOI: 10.1101/gad.1624208. View

19.

Arany Z, Wagner B, Ma Y, Chinsomboon J, Laznik D, Spiegelman B . Gene expression-based screening identifies microtubule inhibitors as inducers of PGC-1alpha and oxidative phosphorylation. Proc Natl Acad Sci U S A. 2008; 105(12):4721-6. PMC: 2290788. DOI: 10.1073/pnas.0800979105. View

20.

Fulco M, Cen Y, Zhao P, Hoffman E, McBurney M, Sauve A . Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev Cell. 2008; 14(5):661-73. PMC: 2431467. DOI: 10.1016/j.devcel.2008.02.004. View