transgenic model to study the pathogenesis of somatic mtDNA mutation accumulation in β-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 mitoch...

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Bibliographic Details
Published in:Diabetes, obesity & metabolism obesity & metabolism, 2007-11, Vol.9 (s2), p.74-80
Main Authors: Bensch, K.G, deGraaf, W, Hansen, P.A, Zassenhaus, H.P, Corbett, J.A
Format: Article
Language:English
Subjects:
Aging - genetics
Animals
Cardiovascular Diseases - genetics
Diabetes Mellitus, Type 2 - genetics
Disease Models, Animal
DNA, Mitochondrial - genetics
Humans
Insulin-Secreting Cells - physiology
MELAS
Mice
Mice, Transgenic
mitochondrial DNA
mtDNA
Mutation
β-cell
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Summary: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 β-cells may be extremely sensitive to the accumulation of mtDNA mutations, as insulin secretion requires the mitochondrial oxidation of glucose to CO₂. Type 2 diabetes arises when β-cells fail to compensate for the increased demand for insulin, and many type 2 diabetics progress to insulin dependence because of a loss of β-cell function or β-cell death. This loss of β-cell function/β-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 β-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.
ISSN:1462-8902
1463-1326
DOI:10.1111/j.1463-1326.2007.00776.x