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Review
. 2011 Jul;1813(7):1269-78.
doi: 10.1016/j.bbamcr.2010.09.019. Epub 2010 Oct 13.

Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network

Richard C Scarpulla  1
Affiliations
Review

Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network

Richard C Scarpulla. Biochim Biophys Acta. 2011 Jul.

Abstract

The PGC-1 family of regulated coactivators, consisting of PGC-1α, PGC-1β and PRC, plays a central role in a regulatory network governing the transcriptional control of mitochondrial biogenesis and respiratory function. These coactivators target multiple transcription factors including NRF-1, NRF-2 and the orphan nuclear hormone receptor, ERRα, among others. In addition, they themselves are the targets of coactivator and co-repressor complexes that regulate gene expression through chromatin remodeling. The expression of PGC-1 family members is modulated by extracellular signals controlling metabolism, differentiation or cell growth and in some cases their activities are known to be regulated by post-translational modification by the energy sensors, AMPK and SIRT1. Recent gene knockout and silencing studies of many members of the PGC-1 network have revealed phenotypes of wide ranging severity suggestive of complex compensatory interactions or broadly integrative functions that are not exclusive to mitochondrial biogenesis. The results point to a central role for the PGC-1 family in integrating mitochondrial biogenesis and energy production with many diverse cellular functions. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.

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Figures

Fig. 1
Fig. 1
Regulatory network governing mitochondrial functions orchestrated by PGC-1α. Interactions among some key participants in the transcriptional network regulating mitochondrial biogenesis are depicted schematically. The diagram summarizes the regulation of PGC-1α by transcriptional and post transcriptional pathways and its interactions with some of its target transcription factors involved in metabolic regulation. Potential suppression of glycolysis through NRF-1 control of VHL expression and negative control by the RIP140 co-repressor are also shown. The specific action of each regulatory factor or pathway is discussed in the text.
Fig. 2
Fig. 2
Arrangement of conserved domains among the PGC-1 family coactivators, PGC-1α, PGC-1β and PRC. Schematic comparison of PGC-1α, PGC-1β and PRC with the identities of the conserved sequence motifs shown in the key at the bottom.
Fig. 3
Fig. 3
A model depicting the integration of mitochondrial and growth regulatory functions by PRC. PRC is rapidly induced by serum stimulation of quiescent cells and down regulated by serum withdrawal or contact inhibition. It binds both NRF-1 and CREB in stimulating the expression of cytochrome c and other genes required for mitochondrial function. It also engages in an indirect, functional interaction with NRF-2 through its binding of host cell factor (HCF). (Binding stoichiometry between NRF-2 and HCF has not been determined experimentally.) Regulation of PRC expression and interactions among transcriptional regulatory factors are discussed in the text.
Fig. 4
Fig. 4
Effects of PRC silencing on mitochondrial morphology and oxidative function. (Panel A) Cytochrome oxidase staining of lentiviral transductants of U2OS cells expressing a control shRNA or PRC shRNA #1. Control shRNA transductants display a more rounded morphology with intense cytochrome oxidase staining of the cytoplasm. PRC shRNA#1 transductants display a flattened morphology with much weaker cytochrome oxidase staining. (Panel B) Electron micrographs of mitochondria from lentiviral transductants of U2OS cells expressing either a control shRNA or PRC shRNAs associated with either complete (shRNA#1) or partial (shRNA#4) PRC silencing. Complete PRC silencing in the PRC shRNA #1 transductant is associated with abundant, atypical mitochondria lacking well defined cristae.
Fig. 5
Fig. 5
Summary of the effects of PRC silencing on the expression of genes required for mitochondrial biogenesis and metabolic function. Genes whose expression is altered significantly (p < 0.01, FDR p < 0.05) upon complete PRC silencing in lentiviral transductants are listed under each functional category. Those up regulated are shown in green while those down regulated are shown in red. Arrows point to a schematic representation of the mitochondrial functions affected.
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