Exploring the role of 4-hydroxy-2-nonenal and mitochondrial dysfunction in diabetic neuropathy

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Akude, Eli Kwaku
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In diabetes hyperglycemia and lack of insulin signaling are key factors in the induction of diabetic sensory neuropathy. The combination of these factors in diabetes may enhance oxidative stress and trigger distal nerve damage in the peripheral nervous system. The link between elevated reactive oxygen species (ROS) levels and nerve degeneration is not clear. We tested the hypothesis that elevation of 4-hydroxy-2-nonenal (4-HNE) induced by oxidative stress in diabetes impairs mitochondrial activity and axonal regeneration in dorsal root ganglion (DRG) neurons. Also, we investigated the association between mitochondrial dysfunction and altered mitochondrial proteome in the axons of streptozotocin–induced diabetic rats. Research design and methods. Cultured adult rat DRG sensory neurons were treated exogenously with 4-HNE, and cell survival, axonal morphology, and level of axon outgrowth assessed. Western blot and fluorescence imaging were used to determine changes in the levels of adducts of 4-HNE and abnormalities in the mitochondria. Proteomic analysis using stable isotope labeling with amino acids in cell culture (SILAC) determined expression of proteins in the mitochondria. Results. 4-HNE impaired axonal regeneration, mitochondrial activity and induced aberrant axonal structures along the axons, which mimicked axon pathology observed in nerve isolated from diabetic rats and replicated aspects of neurodegeneration observed in human diabetic neuropathy. Proteins associated with mitochondrial dysfunction, oxidative phosphorylation and biosynthesis were down regulated in diabetic samples. The axons of diabetic neurons exhibited oxidative stress and depolarized mitochondria. CNTF and resveratrol reversed abnormalities in the mitochondrial membrane potential induced by diabetes and treatment of neurons with 4-HNE. CONCLUSIONS. Elevation of 4-HNE levels in diabetes was associated with impaired mitochondrial function and might be an important link between increased ROS levels and nerve degeneration in diabetic neuropathy. Abnormal mitochondrial function correlated with a down-regulation of mitochondrial proteins, with components of the respiratory chain targeted in lumbar DRG in diabetes. The reduced activity of the respiratory chain was associated with diminished superoxide generation within the mitochondrial matrix and did not contribute to oxidative stress in axons of diabetic neurons.
Mitochondria, Reactive oxygen species (ROS), 4-hydroxy-2-nonenal (4-HNE), Diabetes, Neuropathy
Akude, Eli (2011). Diminished superoxide generation is associated with respiratory chain dysfunction and changes in the mitochondrial proteome of sensory neurons from diabetic rats, Diabetes 60(1):288-97.
Akude, Eli (2010) 4-Hydroxy-2-nonenal induces mitochondrial dysfunction and aberrant axonal outgrowth in adult sensory neurons that mimics features of diabetic neuropathy, Neurotoxicity Research 17(1):28-38