Mitochondrial DNA polymerase editing mutation, Polg ^D257A , reduces the diabetic phenotype of Akita male mice by suppressing appetite

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. D iabetes mellitus is becoming increasingly common worldwide. A large body of data demonstrates links between mitochondrial dysfunction, insulin resistance, and diabetes (1, 2). Deleterious mitochondrial DNA (mtDNA) mutations have their greatest effect in cells that require high energy production, or already have high oxidative stress, including neurons, hair cells of the inner ears, heart and skeletal myocytes, pancreatic beta cells, and gut and kidney epithelial cells (3-7). Complications of diabetes also involve damage to these metabolically active cell types, leading to a hypothesis that mtDNA mutations contributes to the complications. Consistent with these findings, we have demonstrated in mice that a genetic absence of the bradykinin B2 receptor (B2R) combined with diabetes caused by the Akita mutation, Ins2 C96Y

Leydig cell steroidogenesis unexpectedly escapes mitochondrial dysfunction in prematurely aging mice

“…The depletion of germ cells in the testes here and elsewhere (1, 2, 20) was associated with a decreased weight of the epididymis (Fig. 1 D ) and a dramatic decline in the number of spermatozoa therein (Fig.…”

Mouse models of DNA polymerases

“…When crossed with Polg-Akita mice that are associated with hyperglycemia, Polg D257A/D257A /Akita double mutant mice had decreased hyperglycemia. This unexpected finding was attributed to appetite suppression, caused by expression of anorexic genes in the hypothalamus, triggered by a reduced level of testosterone [Fox et al, 2011]. Polg D257A/D257A mice developed cardiomyopathy at 13 to 14 months of age.…”

Cellular Aging Characteristics and Their Association with Age-Related Disorders

“…However, many studies have indicated that mtDNA alteration could be a result of ROS-independent phenomena such as replication errors and failure of the repair mechanisms [73][74][75]. In this context, mice with mtDNA polymerase gamma knock-down (PolgD257A/D275A) have shown somatic mtDNA mutation accumulation and shorter longevity without increasing ROS production [76].…”