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Diabetes regulates mitochondrial biogenesis and fission in mouse neurons.

Research paper by J L JL Edwards, A A Quattrini, S I SI Lentz, C C Figueroa-Romero, F F Cerri, C C Backus, Y Y Hong, E L EL Feldman

Indexed on: 23 Oct '09Published on: 23 Oct '09Published in: Diabetologia



Abstract

Normal mitochondrial activity is a critical component of neuronal metabolism and function. Disruption of mitochondrial activity by altered mitochondrial fission and fusion is the root cause of both neurodegenerative disorders and Charcot-Marie-Tooth type 2A inherited neuropathy. This study addressed the role of mitochondrial fission in the pathogenesis of diabetic neuropathy.Mitochondrial biogenesis and fission were assayed in both in vivo and in vitro models of diabetic neuropathy. Gene, protein, mitochondrial DNA and ultrastructural analyses were used to assess mitochondrial biogenesis and fission.There was greater mitochondrial biogenesis in dorsal root ganglion neurons from diabetic compared with non-diabetic mice. An essential step in mitochondrial biogenesis is mitochondrial fission, regulated by the mitochondrial fission protein dynamin-related protein 1 (DRP1). Evaluation of diabetic neurons in vivo indicated small, fragmented mitochondria, suggesting increased fission. In vitro studies revealed that short-term hyperglycaemic exposure increased levels of DRP1 protein. The influence of hyperglycaemia-mediated mitochondrial fission on cell viability was evaluated by knockdown of Drp1 (also known as Dnm1l). Knockdown of Drp1 resulted in decreased susceptibility to hyperglycaemic damage.We propose that: (1) mitochondria undergo biogenesis in response to hyperglycaemia, but the increased biogenesis is insufficient to accommodate the metabolic load; (2) hyperglycaemia causes an excess of mitochondrial fission, creating small, damaged mitochondria; and (3) reduction of aberrant mitochondrial fission increases neuronal survival and indicates an important role for the fission-fusion equilibrium in the pathogenesis of diabetic neuropathy.