A transgenic model to study the pathogenesis of somatic mtDNA mutation accumulation in beta-cells. Diabetes Obes Metab 2007 Nov;9 Suppl 2:74-80
Date
10/09/2007Pubmed ID
17919181DOI
10.1111/j.1463-1326.2007.00776.xScopus ID
2-s2.0-35148857660 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
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.
Author List
Bensch KG, Degraaf W, Hansen PA, Zassenhaus HP, Corbett JAAuthor
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AgingAnimals
Cardiovascular Diseases
DNA, Mitochondrial
Diabetes Mellitus, Type 2
Disease Models, Animal
Humans
Insulin-Secreting Cells
Mice
Mice, Transgenic
Mutation
