A transgenic model to study the pathogenesis of somatic mtDNA mutation accumulation in beta-cells.
Low levels of somatic mutations accumulate in mitochondrial DNA (mtDNA) as we age; however, the pathogenic nature of these mutations is unknown. In contrast, mutational loads of >30% of mtDNA are associated with electron transport chain defects that result in mitochondrial diseases such as mitochondrial encephalopathy lactic acidosis and stroke-like episodes. Pancreatic beta-cells may be extremely sensitive to the accumulation of mtDNA mutations, as insulin secretion requires the mitochondrial oxidation of glucose to CO(2). Type 2 diabetes arises when beta-cells fail to compensate for the increased demand for insulin, and many type 2 diabetics progress to insulin dependence because of a loss of beta-cell function or beta-cell death. This loss of beta-cell function/beta-cell death has been attributed to the toxic effects of elevated levels of lipids and glucose resulting in the enhanced production of free radicals in beta-cells. mtDNA, localized in close proximity to one of the major cellular sites of free radical production, comprises more than 95% coding sequences such that mutations result in changes in the coding sequence. It has long been known that mtDNA mutations accumulate with age; however, only recently have studies examined the influence of somatic mtDNA mutation accumulation on disease pathogenesis. This article will focus on the effects of low-level somatic mtDNA mutation accumulation on ageing, cardiovascular disease and diabetes.
Bensch
K G
KG
Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St Louis, MO, USA.
Degraaf
W
W
Hansen
P A
PA
Zassenhaus
H P
HP
Corbett
J A
JA
D000375:Aging / Q000235:genetics; D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004195:Disease Models, Animal; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation
D004272:DNA, Mitochondrial