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

Abstract

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% (1.05 mutations/10,000 bp) in islets isolated from transgenic mice. This mutational burden is associated with impaired glucose tolerance and a diabetes prevalence of 52% in male transgenic mice. Female transgenic mice maintain slightly elevated fasting glucose levels, mild glucose intolerance, and a diabetes prevalence of 14%. Diabetes in transgenic animals is associated with insulin insufficiency that results from a significant reduction in beta-cell mass. Importantly, apoptosis of beta-cells is increased 7-fold in female and 11-fold in male transgenic mice compared with littermate controls. These results are consistent with a causative role of somatic mtDNA mutation accumulation in the loss of beta-cell mass and diabetes development.

Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases

“…For example, expression of an exonuclease-deficient Pol γ fusion protein in cultured human cells resulted in the accumulation of mtDNA point mutations (Spelbrink et al, 2000). 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). In mice, transgenic overexpression of exonuclease-deficient Pol γ in cardiac tissue caused a greater than 23-fold increase in mtDNA point mutations and detectable levels of large mtDNA deletions (Zhang et al, 2000).…”

Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations

“…Increased apoptosis occurred by opening of the permeability transition pore causing heart disease; however, the disease is limited by upregulation of Bcl-2 which inhibits pore opening [98–100]. Similarly, transgenic expression of exonuclease-deficient pol γ targeted to pancreatic islet cells led to impaired glucose tolerance, diabetes, and increased apoptosis in β -cells [101, 102]. …”

Hyperinsulinism and Diabetes: Genetic Dissection of β Cell Metabolism-Excitation Coupling in Mice

“…As in other models in which the primary defect is in M-E coupling, older Tfam -mutant mice showed reduced β-cell mass, indicating secondary progression (Silva et al, 2000). Recently, a transgenic mouse expressing mutant mtDNA polymerase γ (D181A polyγ) under insulin promoter-control was generated (Bensch et al, 2009), to cause accumulation of mtDNA mutations in β-cells. Despite males being overtly diabetic and females being glucose-intolerant by 6 weeks of age, GSIS was normal in isolated islets, suggesting a non-islet mechanism.…”