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Journal article
Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy
Proceedings of the National Academy of Sciences - PNAS, v 116(32), pp 16028-16035
06 Aug 2019
PMID: 31253706
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 mitochondria! 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, alpha-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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- Title
- Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy
- Creators
- Piotr K. Kopinski - Howard Hughes Medical InstituteKevin A. Janssen - University of PennsylvaniaPatrick M. Schaefer - Children's Hospital of PhiladelphiaSophie Trefely - Drexel UniversityCaroline E. Perry - Children's Hospital of PhiladelphiaPrasanth Potluri - Children's Hospital of PhiladelphiaJesus A. Tintos-Hernandez - Children's Hospital of PhiladelphiaLarry N. Singh - Children's Hospital of PhiladelphiaKelly R. Karch - University of PennsylvaniaSydney L. Campbell - University of PennsylvaniaMary T. Doan - Drexel UniversityHelen Jiang - Drexel UniversityItzhak Nissim - University of PennsylvaniaEiko Nakamaru-Ogiso - University of PennsylvaniaKathryn E. Wellen - University of PennsylvaniaNathaniel W. Snyder - Drexel UniversityBenjamin A. Garcia - University of PennsylvaniaDouglas C. Wallace - Children's Hospital of Philadelphia
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 116(32), pp 16028-16035
- Publisher
- Natl Acad Sciences
- Number of pages
- 8
- Grant note
- Perelman School of Medicine's Institute for Translational Medicine and Advanced Therapeutics Human Maturational Biology Grant Howard Hughes Medical Institute Research Fellowship Children's Hospital of Philadelphia Foerderer Award W81XWH-16-1-0401 / US Department of Defense; United States Department of Defense NS021328; MH108592; OD010944 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA U54HD086984 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; A.J. Drexel Autism Institute
- Web of Science ID
- WOS:000478971900046
- Scopus ID
- 2-s2.0-85068936137
- Other Identifier
- 991019167967304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Multidisciplinary Sciences