A mithocondrial isoform of P300/CBP associated factor metabolically controls muscle differentiation

Abstract

Histone acetyltransferases (HATs) catalyze the transfer from acetyl-CoA to conserved N-e-lysine residues of both histone and non-histone proteins modulating gene transcription and protein function. P300/CBP-associated factor (PCAF) is known to be involved in activation of the myogenic program, including the regulation of the transcription factor MyoD activity. Recently, it has been shown that the activity of mitochondrial enzymes can be affected by the lysine acetylation/deacetylation process. In C2C12 myoblasts, in fact, the inhibition of Sirtuin 3 (SIRT3) abrogated their terminal differentiation. So far, little is known about the role of HATs and, specifically, that of PCAF in mitochondria during muscle differentiation. Experimental evidence is provided in support of an unprecedented role of PCAF regulating mitochondrial function during skeletal muscle differentiation. Specifically, experiments show that PCAF constitutively localize into the mitochondria regulating lysine acetylation. In this context, co-immunoprecipitations indicated an association of PCAF with the isocitrate dehydrogenase 2 (IDH2) isoform with negative consequences on alpha-ketoglutarate (αKG) production. The depletion of a PCAF putative N-terminal mitochondrial localization sequence or its CRISPR/Cas9 inactivation decreased IDH2 acetylation impacting critically on muscle differentiation in the C2C12 cellular system. Our data suggest that PCAF may be relevant in the epi-metabolic regulation of muscle differentiation