Abstract
Mitochondrial 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.
Highlights
In diabetic subjects, the Mitochondrial DNA (mtDNA) heteroplasmy levels have been reported to be in the range of ~1–45% in leukocytes and ~10–45% in pancreatic β-cells[9,10,11]
We further demonstrate that a coordinate induction of transcriptional regulators of the mitochondrial biogenesis, glucose and fatty acid metabolism pathways underlie the enhanced energy metabolic phenotype of low heteroplasmic mutant cells in contrast to the near homoplasmic mutant cells that lack such a response compared to wild type cells
Previous studies examining the effects of m.3243A > G mutation in cybrids were performed under high glucose conditions[17,32]
Summary
The mtDNA heteroplasmy levels have been reported to be in the range of ~1–45% in leukocytes and ~10–45% in pancreatic β-cells[9,10,11]. We found that the gene expression profiles of mitochondrial OXPHOS, TCA (tri-carboxylic acid) cycle, and FAO (fatty acid oxidation) pathways exhibits marked similarities, the mitochondrial energy metabolic function is discrete in cells harboring either a low or high level of the m.3243A > G mutation compared to wild type cells. We demonstrate that low heteroplasmic mutant cells exhibit a significantly increased mitochondrial bioenergetics, complex IV activity, mtDNA content, endogenous levels of mtDNA encoded transcripts and OXPHOS proteins, as well as an enhanced rate of glucose, pyruvate, and fatty acid oxidation in contrast to the near homoplasmic mutant cells that show a significant mitochondrial functional impairment compared to wild type cells. Our data suggests that the nuclear genome differentially perceives low and high levels of the m.3243A > G mutation and mount a discrete energy metabolic response shedding new insights on the potential mechanisms that may underlie DM pathogenesis
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