Abstract
The impact of mitochondrial dysfunction in epigenetics is emerging, but our understanding of this relationship and its effect on gene expression remains incomplete. We previously showed that acute mitochondrial DNA (mtDNA) loss leads to histone hypoacetylation. It remains to be defined if these changes are maintained when mitochondrial dysfunction is chronic and if they alter gene expression. To fill these gaps of knowledge, we here studied a progressive and a chronic model of mtDNA depletion using biochemical, pharmacological, genomics, and genetic assays. We show that histones are primarily hypoacetylated in both models. We link these effects to decreased histone acetyltransferase activity unrelated to changes in ATP citrate lyase, acetyl coenzyme A synthetase 2, or pyruvate dehydrogenase activities, which can be reversibly modulated by altering the mitochondrial pool of acetyl-coenzyme A. Also, we determined that the accompanying changes in histone acetylation regulate locus-specific gene expression and physiological outcomes, including the production of prostaglandins. These results may be relevant to the pathophysiology of mtDNA depletion syndromes and to understanding the effects of environmental agents that lead to physical or functional mtDNA loss.
Highlights
The role of mitochondria in cell biology and organismal health has expanded dramatically in the last decade
Mitochondrial function is key to organismal health, and it is accepted that mitochondria affect cellular physiology through mechanisms beyond bioenergetics and reactive oxygen species
We previously reported on the link between mitochondrial dysfunction and nuclear DNA hypermethylation (Lozoya et al, 2018) no study so far has demonstrated the requirement of mitochondrial function for long-term maintenance of chromatin acetylation
Summary
The role of mitochondria in cell biology and organismal health has expanded dramatically in the last decade. We first reported that progressive loss of mitochondrial DNA (mtDNA) and the associated changes in TCA cycle output, by ectopically expressing a dominant-negative mtDNA polymerase (DN-POLG), led to histone hypoacetylation in the nucleus (Martinez-Reyes et al, 2016). Using this same cell system, we demonstrated a direct link between loss of mtDNA and DNA hypermethylation, which we showed was driven by modulation of methionine salvage and polyamine synthesis, both sensitive to changes in TCA cycle flux. We showed that DNA methylation changes occurred predominantly at the promoters of genes that responded to mitochondrial dysfunction, increased progressively over the course of mtDNA depletion, and could be reversed by maintaining NADH oxidation in the mitochondria, even in the context of complete mtDNA loss (Lozoya et al, 2018)
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