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While the high mtDNA heteroplasmy exceeding a critical threshold causes\n                    <jats:underline>m<\/jats:underline>\n                    itochondrial\n                    <jats:underline>e<\/jats:underline>\n                    ncephalomyopathy,\n                    <jats:underline>l<\/jats:underline>\n                    actic\n                    <jats:underline>a<\/jats:underline>\n                    cidosis with\n                    <jats:underline>s<\/jats:underline>\n                    troke-like episodes (MELAS) syndrome, the low mtDNA heteroplasmy causes\n                    <jats:underline>m<\/jats:underline>\n                    aternally\n                    <jats:underline>i<\/jats:underline>\n                    nherited\n                    <jats:underline>d<\/jats:underline>\n                    iabetes with or without\n                    <jats:underline>d<\/jats:underline>\n                    eafness (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\u2009A\u2009&gt;\u2009G 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.\n                  <\/jats:p>","DOI":"10.1038\/s41598-019-42262-2","type":"journal-article","created":{"date-parts":[[2019,4,8]],"date-time":"2019-04-08T06:04:10Z","timestamp":1554703450000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Quantitative Variation in m.3243A\u2009&gt;\u2009G Mutation Produce Discrete Changes in Energy Metabolism"],"prefix":"10.1038","volume":"9","author":[{"given":"Ryan P.","family":"McMillan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidney","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Budnick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clayton C.","family":"Caswell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2096-9006","authenticated-orcid":false,"given":"Matthew W.","family":"Hulver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konark","family":"Mukherjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarika","family":"Srivastava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,4,8]]},"reference":[{"key":"42262_CR1","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1146\/annurev.pathol.4.110807.092314","volume":"5","author":"DC Wallace","year":"2010","unstructured":"Wallace, D. 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