Induction of PGC1-Alpha-mediated mitochondrial biogenesis by resveratrol, bezafibrate and AICAR

Overview of the induction of PGC1-α-mediated mitochondrial biogenesis by resveratrol, bezafibrate and AICAR. During caloric excess PGC-1α, the master regulator of mitochondrial biogenesis is in an inactive acetylated (ac) state. In times of caloric restriction, or after exercise, energy becomes scarce resulting in increases in the AMP/ATP ratio and NAD+/NADH ratio. The former has a direct impact on the activation of AMPK as binding of AMP (or ADP) facilitates phosphorylation (p) of AMPK by upstream kinases. Activated AMPK phosphorylates PGC-1α directly, which may either activate this coactivator or prime PGC-1α for activation via deacetylation by SIRT1. SIRT1 requires increased NAD+ levels for its activity as this nucleotide is a cosubstrate of the enzyme. Once in its deacetylated activated form PGC-1α is able to coactivate transcription of nuclear mitochondrial genes via transcription factors including NRF1/2, oestrogen-related receptor (ERR)α,β,γ (ERRs) and PPARα,β,γ. Consequently, this activates the mtDNA transcription, translation and replication machinery (represented by mtDNA); production of OXPHOS subunits; tricarboxylic acid (TCA) cycle enzymes and FAO enzymes. This ultimately leads to mitochondrial proliferation and increased mitochondrial mass. Resveratrol is an activator of SIRT1. The exact mechanism of activation is still unresolved but ultimately results in activation of the PGC-1α pathway via increased deacetylation of the coactivator. AICAR is phosphorylated into its ZMP analogue, an AMP mimetic, and can directly activate AMPK by promoting the phosphorylation of AMPK by upstream kinases. Activation of AMPK causes phosphorylation of PGC-1α, and SIRT1 activation via AMPK-induced increases in the NAD+/NADH ratio. Bezafibrate is a PPAR pan-agonist and therefore able to activate PPAR-regulated gene expression, which includes the expression of PGC-1α via the PPAR-responsive element in its promoter region. The increase in PGC-1α levels is believed to be sufficient for activation of the mitochondrial biogenesis pathway. For more details see the text or reviews (Fernandez-Marcos and Auwerx, ; Scarpulla et al., ; Wenz, ).

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Turn up the power –pharmacological activation of mitochondrial biogenesis in mouse models. (2014) J C Komen, et al. Br J Pharmacol. 2014 Apr;171(8):1818-1836. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

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