Deficiency of the DNA glycosylase OGG1 alters muscle mitochondrial dynamics and predisposes mice to diet‐induced metabolic disease

Abstract

Previous reports have suggested that markers of mitochondrial fission are upregulated in skeletal muscle of mouse models of obesity. However, the precise mechanisms mediating this change in mitochondrial morphology have not yet been elucidated, and damage to cellular DNA due to oxidative stress has not been investigated as a causal factor in the maintenance of mitochondrial dynamics. We have recently demonstrated that mice lacking the DNA repair glycosylase OGG1, which repairs the major oxidative DNA lesion 8‐OH‐dG, unexpectedly develop obesity and other features of metabolic syndrome upon being fed a high‐fat diet (HFD). Interestingly, while wild‐type mice upregulate mitochondrial fission genes only upon being fed a HFD, Ogg1−/− mice display increased expression of these genes even under chowfed conditions. This alteration in mitochondrial dynamics in Ogg1−/− mice occurs in the absence of changes in body weight or fat mass and is accompanied by a significant reduction in grip strength and an increased propensity to diet‐induced insulin resistance. Feeding Ogg1−/− mice a HFD does not further increase the expression of these key regulators, including dynamin‐related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1), suggesting that oxidative DNA damage alone may play a pivotal role in maintaining the mitochondrial network in skeletal muscle and whole body metabolic homeostasis. Support: AHA 11POST7480004 to HS, NIH RO1 DK075974 to RSL