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Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy

Diseases associated with mitochondrial DNA (mtDNA) mutations are highly variable in phenotype, in large part because of differences in the percentage of normal and mutant mtDNAs (heteroplasmy) present within the cell. For example, increasing heteroplasmy levels of the mtDNA tRNA(Leu(UUR)) nucleotide...

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Autores principales: Kopinski, Piotr K., Janssen, Kevin A., Schaefer, Patrick M., Trefely, Sophie, Perry, Caroline E., Potluri, Prasanth, Tintos-Hernandez, Jesus A., Singh, Larry N., Karch, Kelly R., Campbell, Sydney L., Doan, Mary T., Jiang, Helen, Nissim, Itzhak, Nakamaru-Ogiso, Eiko, Wellen, Kathryn E., Snyder, Nathaniel W., Garcia, Benjamin A., Wallace, Douglas C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689928/
https://www.ncbi.nlm.nih.gov/pubmed/31253706
http://dx.doi.org/10.1073/pnas.1906896116
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author Kopinski, Piotr K.
Janssen, Kevin A.
Schaefer, Patrick M.
Trefely, Sophie
Perry, Caroline E.
Potluri, Prasanth
Tintos-Hernandez, Jesus A.
Singh, Larry N.
Karch, Kelly R.
Campbell, Sydney L.
Doan, Mary T.
Jiang, Helen
Nissim, Itzhak
Nakamaru-Ogiso, Eiko
Wellen, Kathryn E.
Snyder, Nathaniel W.
Garcia, Benjamin A.
Wallace, Douglas C.
author_facet Kopinski, Piotr K.
Janssen, Kevin A.
Schaefer, Patrick M.
Trefely, Sophie
Perry, Caroline E.
Potluri, Prasanth
Tintos-Hernandez, Jesus A.
Singh, Larry N.
Karch, Kelly R.
Campbell, Sydney L.
Doan, Mary T.
Jiang, Helen
Nissim, Itzhak
Nakamaru-Ogiso, Eiko
Wellen, Kathryn E.
Snyder, Nathaniel W.
Garcia, Benjamin A.
Wallace, Douglas C.
author_sort Kopinski, Piotr K.
collection PubMed
description Diseases associated with mitochondrial DNA (mtDNA) mutations are highly variable in phenotype, in large part because of differences in the percentage of normal and mutant mtDNAs (heteroplasmy) present within the cell. For example, increasing heteroplasmy levels of the mtDNA tRNA(Leu(UUR)) nucleotide (nt) 3243A > G mutation result successively in diabetes, neuromuscular degenerative disease, and perinatal lethality. These phenotypes are associated with differences in mitochondrial function and nuclear DNA (nDNA) gene expression, which are recapitulated in cybrid cell lines with different percentages of m.3243G mutant mtDNAs. Using metabolic tracing, histone mass spectrometry, and NADH fluorescence lifetime imaging microscopy in these cells, we now show that increasing levels of this single mtDNA mutation cause profound changes in the nuclear epigenome. At high heteroplasmy, mitochondrially derived acetyl-CoA levels decrease causing decreased histone H4 acetylation, with glutamine-derived acetyl-CoA compensating when glucose-derived acetyl-CoA is limiting. In contrast, α-ketoglutarate levels increase at midlevel heteroplasmy and are inversely correlated with histone H3 methylation. Inhibition of mitochondrial protein synthesis induces acetylation and methylation changes, and restoration of mitochondrial function reverses these effects. mtDNA heteroplasmy also affects mitochondrial NAD(+)/NADH ratio, which correlates with nuclear histone acetylation, whereas nuclear NAD(+)/NADH ratio correlates with changes in nDNA and mtDNA transcription. Thus, mutations in the mtDNA cause distinct metabolic and epigenomic changes at different heteroplasmy levels, potentially explaining transcriptional and phenotypic variability of mitochondrial disease.
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spelling pubmed-66899282019-08-14 Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy Kopinski, Piotr K. Janssen, Kevin A. Schaefer, Patrick M. Trefely, Sophie Perry, Caroline E. Potluri, Prasanth Tintos-Hernandez, Jesus A. Singh, Larry N. Karch, Kelly R. Campbell, Sydney L. Doan, Mary T. Jiang, Helen Nissim, Itzhak Nakamaru-Ogiso, Eiko Wellen, Kathryn E. Snyder, Nathaniel W. Garcia, Benjamin A. Wallace, Douglas C. Proc Natl Acad Sci U S A PNAS Plus Diseases associated with mitochondrial DNA (mtDNA) mutations are highly variable in phenotype, in large part because of differences in the percentage of normal and mutant mtDNAs (heteroplasmy) present within the cell. For example, increasing heteroplasmy levels of the mtDNA tRNA(Leu(UUR)) nucleotide (nt) 3243A > G mutation result successively in diabetes, neuromuscular degenerative disease, and perinatal lethality. These phenotypes are associated with differences in mitochondrial function and nuclear DNA (nDNA) gene expression, which are recapitulated in cybrid cell lines with different percentages of m.3243G mutant mtDNAs. Using metabolic tracing, histone mass spectrometry, and NADH fluorescence lifetime imaging microscopy in these cells, we now show that increasing levels of this single mtDNA mutation cause profound changes in the nuclear epigenome. At high heteroplasmy, mitochondrially derived acetyl-CoA levels decrease causing decreased histone H4 acetylation, with glutamine-derived acetyl-CoA compensating when glucose-derived acetyl-CoA is limiting. In contrast, α-ketoglutarate levels increase at midlevel heteroplasmy and are inversely correlated with histone H3 methylation. Inhibition of mitochondrial protein synthesis induces acetylation and methylation changes, and restoration of mitochondrial function reverses these effects. mtDNA heteroplasmy also affects mitochondrial NAD(+)/NADH ratio, which correlates with nuclear histone acetylation, whereas nuclear NAD(+)/NADH ratio correlates with changes in nDNA and mtDNA transcription. Thus, mutations in the mtDNA cause distinct metabolic and epigenomic changes at different heteroplasmy levels, potentially explaining transcriptional and phenotypic variability of mitochondrial disease. National Academy of Sciences 2019-08-06 2019-06-28 /pmc/articles/PMC6689928/ /pubmed/31253706 http://dx.doi.org/10.1073/pnas.1906896116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Kopinski, Piotr K.
Janssen, Kevin A.
Schaefer, Patrick M.
Trefely, Sophie
Perry, Caroline E.
Potluri, Prasanth
Tintos-Hernandez, Jesus A.
Singh, Larry N.
Karch, Kelly R.
Campbell, Sydney L.
Doan, Mary T.
Jiang, Helen
Nissim, Itzhak
Nakamaru-Ogiso, Eiko
Wellen, Kathryn E.
Snyder, Nathaniel W.
Garcia, Benjamin A.
Wallace, Douglas C.
Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy
title Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy
title_full Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy
title_fullStr Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy
title_full_unstemmed Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy
title_short Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy
title_sort regulation of nuclear epigenome by mitochondrial dna heteroplasmy
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689928/
https://www.ncbi.nlm.nih.gov/pubmed/31253706
http://dx.doi.org/10.1073/pnas.1906896116
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