Reactome | Mitochondrial biogenesis

Mitochondrial biogenesis

Stable Identifier

R-HSA-1592230

DOI

10.3180/REACT_200788.1

Type

Pathway

Species

Homo sapiens

Compartment

cytosol, mitochondrial matrix, nucleoplasm

ReviewStatus

5/5

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Mitochondrial biogenesis and remodeling occur in response to exercise and redox state (reviewed in Scarpulla et al. 2012, Handy and Loscalzo 2012, Piantadosi and Suliman 2012, Scarpulla 2011, Wenz et al. 2011, Bo et al. 2010, Jornayvaz and Shulman 2010, Ljubicic et al. 2010, Hock and Kralli 2009, Canto and Auwerx 2009, Lin 2009, Scarpulla 2008, Ventura-Clapier et al. 2008). It is hypothesized that calcium influx and energy depletion are the signals that initiate changes in gene expression leading to new mitochondrial proteins. Energy depletion causes a reduction in ATP and an increase in AMP which activates AMPK. AMPK in turn phosphorylates the coactivator PGC-1alpha (PPARGC1A), one of the master regulators of mitochondrial biosynthesis. Likewise, p38 MAPK is activated by muscle contraction (possibly via calcium and CaMKII) and phosphorylates PGC-1alpha. CaMKIV responds to intracellular calcium by phosphorylating CREB, which activates expression of PGC-1alpha.
Deacetylation of PGC-1alpha by SIRT1 may also play a role in activation (Canto et al. 2009, Gurd et al. 2011), however Sirt11 deacetylation of Ppargc1a in mouse impacted genes related to glucose metabolism rather than mitochondrial biogenesis (Rodgers et al. 2005) and mice lacking SIRT1 in muscle had normal levels of mitochondrial biogenesis in response to exercise (Philp et al. 2011) so the role of deacetylation is not fully defined. PGC-1beta and PPRC appear to act similarly to PGC-1alpha but they have not been as well studied.
Phosphorylated PGC-1alpha does not bind DNA directly but instead interacts with other transcription factors, notably NRF1 and NRF2 (via HCF1). NRF1 and NRF2 together with PGC-1alpha activate the transcription of nuclear-encoded, mitochondrially targeted proteins such as TFB2M, TFB1M, and TFAM.

Literature References

PubMed ID	Title	Journal	Year
19262508	AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity Cantó, C, Gerhart-Hines, Z, Feige, JN, Lagouge, M, Noriega, L, Milne, JC, Elliott, PJ, Puigserver, P, Auwerx, J	Nature	2009
15744310	Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1 Rodgers, JT, Lerin, C, Haas, W, Gygi, SP, Spiegelman, BM, Puigserver, P	Nature	2005
21757760	Sirtuin 1 (SIRT1) Deacetylase Activity Is Not Required for Mitochondrial Biogenesis or Peroxisome Proliferator-activated Receptor-{gamma} Coactivator-1{alpha} (PGC-1{alpha}) Deacetylation following Endurance Exercise Philp, A, Chen, A, Lan, D, Meyer, GA, Murphy, AN, Knapp, AE, Olfert, IM, McCurdy, CE, Marcotte, GR, Hogan, MC, Baar, K, Schenk, S	J Biol Chem	2011
20649548	Redefining the role of mitochondria in exercise: a dynamic remodeling Bo, H, Zhang, Y, Ji, LL	Ann. N. Y. Acad. Sci.	2010
22817841	Transcriptional integration of mitochondrial biogenesis Scarpulla, RC, Vega, RB, Kelly, DP	Trends Endocrinol. Metab.	2012
19276888	PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure Cantó, C, Auwerx, J	Curr Opin Lipidol	2009
21629705	Mitochondria and PGC-1? in Aging and Age-Associated Diseases Wenz, T	J Aging Res	2011
22146081	Redox regulation of mitochondrial function Handy, DE, Loscalzo, J	Antioxid. Redox Signal.	2012
19575678	Transcriptional control of mitochondrial biogenesis and function Hock, MB, Kralli, A	Annu Rev Physiol	2009
22265687	Transcriptional control of mitochondrial biogenesis and its interface with inflammatory processes Piantadosi, CA, Suliman, HB	Biochim. Biophys. Acta	2012
19682549	Transcriptional and post-transcriptional regulation of mitochondrial biogenesis in skeletal muscle: effects of exercise and aging Ljubicic, V, Joseph, AM, Saleem, A, Uguccioni, G, Collu-Marchese, M, Lai, RY, Nguyen, LM, Hood, DA	Biochim Biophys Acta	2010
19076454	Nuclear control of respiratory chain expression by nuclear respiratory factors and PGC-1-related coactivator Scarpulla, RC	Ann N Y Acad Sci	2008
21543634	Nuclear SIRT1 activity, but not protein content, regulates mitochondrial biogenesis in rat and human skeletal muscle Gurd, BJ, Yoshida, Y, McFarlan, JT, Holloway, GP, Moyes, CD, Heigenhauser, GJ, Spriet, L, Bonen, A	Am J Physiol Regul Integr Comp Physiol	2011
20533901	Regulation of mitochondrial biogenesis Jornayvaz, FR, Shulman, GI	Essays Biochem.	2010
20933024	Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network Scarpulla, RC	Biochim Biophys Acta	2011
19008463	Minireview: the PGC-1 coactivator networks: chromatin-remodeling and mitochondrial energy metabolism Lin, JD	Mol. Endocrinol.	2009
18430751	Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha Ventura-Clapier, R, Garnier, A, Veksler, V	Cardiovasc. Res.	2008