Quantitative Variation in m.3243A > G Mutation Produce Discrete Changes in Energy Metabolism

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dc.contributor.authorMcMillan, Ryan P.en
dc.contributor.authorStewart, Sidneyen
dc.contributor.authorBudnick, James A.en
dc.contributor.authorCaswell, Clayton C.en
dc.contributor.authorHulver, Matthew W.en
dc.contributor.authorMukherjee, Konarken
dc.contributor.authorSrivastava, Sarikaen
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.contributor.departmentHuman Nutrition, Foods, and Exerciseen
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.date.accessioned2019-07-23T16:50:04Zen
dc.date.available2019-07-23T16:50:04Zen
dc.date.issued2019-04-08en
dc.description.abstractMitochondrial DNA (mtDNA) 3243A > G tRNALeu((UUR)) heteroplasmic mutation (m.3243A > G) exhibits clinically heterogeneous phenotypes. While the high mtDNA heteroplasmy exceeding a critical threshold causes mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome, the low mtDNA heteroplasmy causes maternally inherited diabetes with or without deafness (MIDD) syndrome. How quantitative differences in mtDNA heteroplasmy produces distinct pathological states has remained elusive. Here we show that despite striking similarities in the energy metabolic gene expression signature, the mitochondrial bioenergetics, biogenesis and fuel catabolic functions are distinct in cells harboring low or high levels of the m.3243 A > G mutation compared to wild type cells. We further demonstrate that the low heteroplasmic mutant cells exhibit a coordinate induction of transcriptional regulators of the mitochondrial biogenesis, glucose and fatty acid metabolism pathways that lack in near homoplasmic mutant cells compared to wild type cells. Altogether, these results shed new biological insights on the potential mechanisms by which low mtDNA heteroplasmy may progressively cause diabetes mellitus.en
dc.description.notesWe thank Yaru Wu and Vrushali Chavan for providing the technical assistance. This work was supported by Virginia Tech open access subvention fund.en
dc.description.sponsorshipVirginia Tech open access subvention funden
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41598-019-42262-2en
dc.identifier.issn2045-2322en
dc.identifier.other5752en
dc.identifier.pmid30962477en
dc.identifier.urihttp://hdl.handle.net/10919/91924en
dc.identifier.volume9en
dc.language.isoenen
dc.publisherSpringer Natureen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectmitochondrial-dna mutationen
dc.subjectmolecular-mechanismsen
dc.subjectrespiratory-functionen
dc.subjectclinical-featuresen
dc.subjectdiabetes-mellitusen
dc.subjectheteroplasmyen
dc.subjectgeneen
dc.subjectmelasen
dc.subjectbioenergeticsen
dc.subjectcellsen
dc.titleQuantitative Variation in m.3243A > G Mutation Produce Discrete Changes in Energy Metabolismen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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