TY - JOUR
T1 - Mitochondrial acetyl-CoA reversibly regulates locusspecific histone acetylation and gene expression
AU - Lozoya, Oswaldo A.
AU - Wang, Tianyuan
AU - Grenet, Dagoberto
AU - Wolfgang, Taylor C.
AU - Sobhany, Mack
AU - Da Silva, Douglas Ganini
AU - Riadi, Gonzalo
AU - Chandel, Navdeep
AU - Woychik, Richard P.
AU - Santos, Janine H.
N1 - Funding Information:
We thank the staff at the Core Facilities at National Institute of Environmental Health Sciences (NIEHS) and National Institutes of Health (NIH) (Epigenetics and Genomics) and the critical reading of the manuscript by Drs. Matthew Longley and Robert Petrovich (NIEHS). We also thank Dr. Jia-Ji Lin (NIEHS) for help with the hypoxic experiments. This research was supported by the Intramural Research Program of the NIH, NIEHS.
Publisher Copyright:
© 2019 Lozoya et al.
PY - 2019/2
Y1 - 2019/2
N2 - 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.
AB - 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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U2 - 10.26508/LSA.201800228
DO - 10.26508/LSA.201800228
M3 - Article
C2 - 30737248
AN - SCOPUS:85067617554
VL - 2
JO - Life Science Alliance
JF - Life Science Alliance
SN - 2575-1077
IS - 1
M1 - e201800228
ER -