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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Life Science Alliance LLC
2019
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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. |
format | Online Article Text |
id | pubmed-6369536 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Life Science Alliance LLC |
record_format | MEDLINE/PubMed |
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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