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% (1.05 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.
Bensch
Kenneth G
KG
Edward A Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, MO 63104, USA.
Mott
Justin L
JL
Chang
Shin-Wen
SW
Hansen
Polly A
PA
Moxley
Michael A
MA
Chambers
Kari T
KT
de Graaf
Wieke
W
Zassenhaus
H Peter
HP
Corbett
John A
JA
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D003920:Diabetes Mellitus / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology*; D009929:Organ Size; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D019076:Transgenes / Q000502:physiology
D004272:DNA, Mitochondrial; D007328:Insulin; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse; D005947:Glucose