Selective mtDNA mutation accumulation results in beta-cell apoptosis and diabetes development.

To test the hypothesis that somatic mitochondrial (mt)DNA mutation accumulation predisposes mice to beta-cell loss and diabetes development, transgenic mice expressing a proofreading-deficient mtDNA polymerase-gamma under the control of the rat insulin-1 promoter were generated. At 6 wk of age, mtDNA mutations reached 0.01% (1.

Mitochondrial DNA mutations may contribute to aging via cell death caused by peptides that induce cytochrome c release.

Mice wherein the wild-type mitochondrial DNA polymerase (pol gamma) is replaced by a proofreading-deficient version are born with mutation frequencies in mitochondrial DNA (mtDNA) much higher than are ever normally seen in old rodents or humans. These mice, however, are phenotypically normal at birth, raising the question regarding how the much lower frequencies observed in normal aging could possibly contribute to the aging process. In contrast, transgenic mice with cardiac-specific expression of a proofreading-deficient poly gamma from birth onwards accumulate mtDNA mutations to levels normally seen in aging.

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).

Mitochondrial DNA mutations cause resistance to opening of the permeability transition pore.

The age-related accumulation of mitochondrial DNA mutations has the potential to impair organ function and contribute to disease. In support of this hypothesis, accelerated mitochondrial mutagenesis is pathogenic in the mouse heart, and there is an increase in myocyte apoptosis. The current study sought to identify functional alterations in cell death signaling via mitochondria.

Mitochondrial DNA mutations, apoptosis, and the misfolded protein response.

Studies of transgenic mice with accelerated accumulation of mtDNA mutations specifically in the heart lead us to propose that apoptotic signaling and cell death is central to the pathogenesis of mtDNA mutations in aging. It is the cellular response to that apoptotic signaling and the organ?s compensatory response to a loss of cells that specify the phenotype of an accumulation of mtDNA mutations. In the heart, cardiomyocytes induce a vigorous anti-apoptotic, pro-survival response to counteract mitochondrial apoptotic signaling.