The role of mitochondria in regulating the epigenome and transcriptome

Abstract

Mitochondria are well-recognized for their role in ATP and reactive oxygen species generation, in addition to producing intermediate metabolites through the TCA (tricarboxylic acid) cycle. We recently showed in an acute model of mitochondrial DNA (mtDNA) depletion that electron flow sustains a functional oxidative TCA cycle, which in turn is necessary to maintain histone acetylation. The exact metabolite(s) involved in these effects and whether mitochondrial-driven histone changes suffice to alter gene expression remain ill defined. In this study, we capitalized on a well-characterized cell culture model of chronic mtDNA depletion, which best recapitulates disease conditions associated with mitochondrial dysfunction, to define these issues. Using a suit of biochemical, metabolic and genomic approaches, here we show that mitochondrial-derived acetyl-CoA is required to maintain histone acetyl transferase (HAT) activity and nuclear histone acetylation. RNA-seq, ChIP-seq and DNA methylation arrays reveal that the loss of mitochondrial acetyl-CoA results in differential gene expression that is largely (~30%) coordinated by epigenetic alterations. In addition, a set of specific upstream regulators seemingly sensitive to changes in the cellular acetyl-CoA pool seem also to be important. Collectively, our data point to the requirement of a mitochondrial metabolites to maintain the epigenome, revealing yet another layer through which mitochondria dysfunction can affect organismal development and health outcomes.