Mitochondrial DNA polymerase editing mutation, PolgD257A, reduces the diabetic
phenotype of Akita male mice by suppressing appetite.
Authors Fox R, Kim HS, Reddick RL, Kujoth GC, Prolla TA, Tsutsumi S, Wada Y, Smithies O,
Maeda N
Submitted By Nobuyo Maeda on 2/22/2012
Status Published
Journal Proceedings of the National Academy of Sciences of the United States of America
Year 2011
Date Published 5/24/2011
Volume : Pages 108 : 8779 - 8784
PubMed Reference 21555558
Abstract Diabetes and the development of its complications have been associated with
mitochondrial DNA (mtDNA) dysfunction, but causal relationships remain
undetermined. With the objective of testing whether increased mtDNA mutations
exacerbate the diabetic phenotype, we have compared mice heterozygous for the
Akita diabetogenic mutation (Akita) with mice homozygous for the D257A mutation
in mitochondrial DNA polymerase gamma (Polg) or with mice having both mutations
(Polg-Akita). The Polg-D257A protein is defective in proofreading and increases
mtDNA mutations. At 3 mo of age, the Polg-Akita and Akita male mice were equally
hyperglycemic. Unexpectedly, as the Polg-Akita males aged to 9 mo, their
diabetic symptoms decreased. Thus, their hyperglycemia, hyperphagia and urine
output declined significantly. The decrease in their food intake was accompanied
by increased plasma leptin and decreased plasma ghrelin, while hypothalamic
expression of the orexic gene, neuropeptide Y, was lower and expression of the
anorexic gene, proopiomelanocortin, was higher. Testis function progressively
worsened with age in the double mutants, and plasma testosterone levels in
9-mo-old Polg-Akita males were significantly reduced compared with Akita males.
The hyperglycemia and hyperphagia returned in aged Polg-Akita males after
testosterone administration. Hyperglycemia-associated distal tubular damage in
the kidney also returned, and Polg-D257A-associated proximal tubular damage was
enhanced. The mild diabetes of female Akita mice was not affected by the
Polg-D257A mutation. We conclude that reduced diabetic symptoms of aging
Polg-Akita males results from appetite suppression triggered by decreased
testosterone associated with damage to the Leydig cells of the testis.

Investigators with authorship
Nobuyo MaedaUniversity of North Carolina
Oliver SmithiesUniversity of North Carolina