Diabetes regulates mitochondrial biogenesis and fission in mouse neurons.
Authors Edwards JL, Quattrini A, Lentz SI, Figueroa-Romero C, Cerri F, Backus C, Hong Y,
Feldman EL
Submitted By Oliver Smithies on 3/24/2010
Status Published
Journal Diabetologia
Year 2010
Date Published 1/1/2010
Volume : Pages 53(1) : 160 - 169
PubMed Reference 19847394
Abstract 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.


Dapk2death-associated kinase 2
Dnm1dynamin 1
Dnm1ldynamin 1-like
Crmp1collapsin response mediator protein 1