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A transgenic model to study the pathogenesis of somatic mtDNA mutation accumulation in β‐cells
Author(s) -
Bensch K. G.,
DeGraaf W.,
Hansen P. A.,
Zassenhaus H. P.,
Corbett J. A.
Publication year - 2007
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2007.00776.x
Subject(s) - mitochondrial dna , somatic cell , biology , mutation , mitochondrion , beta cell , lactic acidosis , mutation accumulation , germline mutation , pathogenesis , genetics , insulin , gene , endocrinology , mutation rate , immunology , islet
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 CO 2 . 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.