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Mitochondrial Acetyl-CoA Reversibly Regulates Locus-specific Histone Acetylation And Gene Expression

O. Lozoya, Tianyuan Wang, D. Grenet, Taylor C Wolfgang, M. Sobhany, D. Ganini da Silva, Gonzalo Riadi, N. Chandel, R. Woychik, J. Santos
Published 2019 · Medicine, Chemistry

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This study shows that genetic or pharmacological manipulation of the TCA cycle, when mitochondria are dysfunctional, can modulate histone acetylation and gene expression in the nucleus with physiological outcomes. 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.
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