PT  - JOURNAL ARTICLE
AU  - Oswaldo A. Lozoya
AU  - Tianyuan Wang
AU  - Dagoberto Grenet
AU  - Taylor C. Wolfgang
AU  - Mack Sobhany
AU  - Douglas Ganini da Silva
AU  - Gonzalo Riadi
AU  - Navdeep Chandel
AU  - Richard P. Woychik
AU  - Janine H. Santos
TI  - Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression
AID  - 10.1101/380261
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 380261
4099  - http://biorxiv.org/content/early/2018/07/30/380261.short
4100  - http://biorxiv.org/content/early/2018/07/30/380261.full
AB  - The impact of mitochondria in epigenetics is emerging but our understanding of this relationship and its impact on gene expression remain 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, importantly, if they are sufficient to alter gene expression. To fill these gaps, we here studied both a progressive and a chronic model of mtDNA depletion using biochemical, pharmacological, genomics and genetic assays. We show that histones are hypoacetylated in both models. We link these effects to decreased histone acetyltransferase (HAT) activity independent of changes in ATP citrate lyase function, which can be reversibly modulated by altering specifically the mitochondrial pool of acetyl-CoA. Also, we determined that these changes 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, such as AZT or antibiotics, that lead to physical or functional mtDNA loss.