A transgenic model to study the pathogenesis of somatic mtDNA mutation accumulation in β‐cells
Abstract
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.
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Exonuclease-deficient Pol γ in pancreatic islet cells caused impaired glucose tolerance, diabetes, and increased apoptosis in β-cells.
“Exonuclease-deficient Pol γ pancreatic islet cells caused impaired glucose tolerance, diabetes, and increased apoptosis in β-cells (Bensch et al., 2007; Bensch et al., 2009).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Bensch et al., 2007
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- Authors
- Bensch, K. G., DeGraaf, W., Hansen, P. A., Zassenhaus, H. P., & Corbett, J. A.
- Affiliations
- Saint Louis University (US)
- Corresponding author
- Corbett, J. A.
- Venue
- Diabetes Obesity and Metabolism
- Publisher
- Wiley
- Published
- 2007-10-04
- Volume
- 9
- Issue
- s2
- Pages
- 74-80
- ISSN
- 1462-8902 (ISSN-L)
- 1463-1326
- OpenAlex
- W2046073736
- Cited by
- 12
- References
- 38
- Citations by year
- 2025: 1 · 2020: 1 · 2017: 1 · 2016: 1
- FWCI
- 1.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes Obesity and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5f30ag029104-02)
- National Institute on Aging (AG029104)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- somatic mtDNA mutations, mitochondrial DNA, pancreatic beta cells, type 2 diabetes, beta-cell death, aging, mitochondrial disease, mitochondrial encephalomyopathy, free radicals, transgenic mouse model, cardiovascular disease, insulin secretion
- MeSH terms
- Aging, Animals, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Disease Models, Animal, DNA, Mitochondrial, Humans, Mice, Transgenic, Mutation, Insulin-Secreting Cells, Mice
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