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Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy. | LitMetric

AI Article Synopsis

  • Mitochondrial DNA (mtDNA) mutations lead to varying diseases based on the proportion of normal vs. mutant mtDNA (heteroplasmy), influencing phenotypes like diabetes and neuromuscular disorders.
  • Studies show that different levels of a specific mtDNA mutation alter the nuclear epigenome and mitochondrial function, affecting histone acetylation and methylation.
  • Changes in the NAD/NADH ratios in mitochondria and the nucleus are connected to these epigenomic alterations, helping to explain why mitochondrial diseases can have such diverse symptoms.

Article 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 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689928PMC
http://dx.doi.org/10.1073/pnas.1906896116DOI Listing

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