CMT 2A: Diabetes regulates mitochondrial biogenesis and fission in mouse neurons

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Diabetologia. 2009 Oct 22.

Diabetes regulates mitochondrial biogenesis and fission in mouse neurons.

JL, Quattrini A, Lentz SI, Figueroa-Romero C, Cerri F, Backus C, Hong Y,

Feldman EL.

Department of Neurology, University of Michigan, 5017 BSRB, 109 Zina Pitcher

Place, Ann Arbor, MI, 48109, USA.

AIMS/HYPOTHESIS: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS/INTERPRETATION: 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.