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Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression

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 chan...

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Autores principales: Lozoya, Oswaldo A, Wang, Tianyuan, Grenet, Dagoberto, Wolfgang, Taylor C, Sobhany, Mack, Ganini da Silva, Douglas, Riadi, Gonzalo, Chandel, Navdeep, Woychik, Richard P, Santos, Janine H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369536/
https://www.ncbi.nlm.nih.gov/pubmed/30737248
http://dx.doi.org/10.26508/lsa.201800228
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author Lozoya, Oswaldo A
Wang, Tianyuan
Grenet, Dagoberto
Wolfgang, Taylor C
Sobhany, Mack
Ganini da Silva, Douglas
Riadi, Gonzalo
Chandel, Navdeep
Woychik, Richard P
Santos, Janine H
author_facet Lozoya, Oswaldo A
Wang, Tianyuan
Grenet, Dagoberto
Wolfgang, Taylor C
Sobhany, Mack
Ganini da Silva, Douglas
Riadi, Gonzalo
Chandel, Navdeep
Woychik, Richard P
Santos, Janine H
author_sort Lozoya, Oswaldo A
collection PubMed
description 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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spelling pubmed-63695362019-02-15 Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression Lozoya, Oswaldo A Wang, Tianyuan Grenet, Dagoberto Wolfgang, Taylor C Sobhany, Mack Ganini da Silva, Douglas Riadi, Gonzalo Chandel, Navdeep Woychik, Richard P Santos, Janine H Life Sci Alliance Research Articles 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. Life Science Alliance LLC 2019-02-08 /pmc/articles/PMC6369536/ /pubmed/30737248 http://dx.doi.org/10.26508/lsa.201800228 Text en © 2019 Lozoya et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Lozoya, Oswaldo A
Wang, Tianyuan
Grenet, Dagoberto
Wolfgang, Taylor C
Sobhany, Mack
Ganini da Silva, Douglas
Riadi, Gonzalo
Chandel, Navdeep
Woychik, Richard P
Santos, Janine H
Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression
title Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression
title_full Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression
title_fullStr Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression
title_full_unstemmed Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression
title_short Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression
title_sort mitochondrial acetyl-coa reversibly regulates locus-specific histone acetylation and gene expression
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369536/
https://www.ncbi.nlm.nih.gov/pubmed/30737248
http://dx.doi.org/10.26508/lsa.201800228
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