Redox regulation of mitochondrial fission, protein misfolding, synaptic damage, and neuronal cell death: potential implications for Alzheimer’s and Parkinson’s diseases

Normal mitochondrial dynamics consist of fission and fusion events giving rise to new mitochondria, a process termed mitochondrial biogenesis. However, several neurodegenerative disorders manifest aberrant mitochondrial dynamics, resulting in morphological abnormalities often associated with deficits in mitochondrial mobility and cell bioenergetics. Rarely, dysfunctional mitochondrial occur in a familial pattern due to genetic mutations, but much more commonly patients manifest sporadic forms of mitochondrial disability presumably related to a complex set of interactions of multiple genes (or their products) with environmental factors (G × E). Recent studies have shown that generation of excessive nitric oxide (NO), in part due to generation of oligomers of amyloid-β (Aβ) protein or overactivity of the NMDA-subtype of glutamate receptor, can augment mitochondrial fission, leading to frank fragmentation of the mitochondria. S-Nitrosylation, a covalent redox reaction of NO with specific protein thiol groups, represents one mechanism contributing to NO-induced mitochondrial fragmentation, bioenergetic failure, synaptic damage, and eventually neuronal apoptosis. Here, we summarize our evidence in Alzheimer’s disease (AD) patients and animal models showing that NO contributes to mitochondrial fragmentation via S-nitrosylation of dynamin-related protein 1 (Drp1), a protein involved in mitochondrial fission. These findings may provide a new target for drug development in AD. Additionally, we review emerging evidence that redox reactions triggered by excessive levels of NO can contribute to protein misfolding, the hallmark of a number of neurodegenerative disorders, including AD and Parkinson’s disease. For example, S-nitrosylation of parkin disrupts its E3 ubiquitin ligase activity, and thereby affects Lewy body formation and neuronal cell death

Extracellular-Nitric Oxide-Mediated Platelet-cGMP Production in Type 2 Diabetics Correlates Inversely with Plasma Membrane Cholesterol Levels

Recently, we showed that the diffusion of nitric oxide (NO) and NO-mediated signaling was affected by the levels of plasma membrane cholesterol in fibroblasts. The generality of these observations, which would imply that perturbations in NO-signaling mediated by increased membrane cholesterol levels, could be a common pathological trigger in vascular cells, was tested in platelets from normal and dyslipidemic type 2 diabetic (T2D) subjects. Plasma LDL-cholesterol correlated directly with platelet plasma membrane cholesterol (Y=0.28X+0.16; R2=0.39). The average platelet plasma membrane cholesterol concentration was ~2-fold larger in T2D than in control subjects (P<0.05). Cyclic GMP production in response to exogenous NO was ~4-fold larger in controls than in T2D (P<0.05). Artificial elevation of membrane cholesterol resulted in ~50 % decrease in the initial rates of NO-uptake. Elevated plasma cholesterol could be a contributing factor to T2D-induced platelet hyperactivity, since it correlated with increased plasma membrane cholesterol, the attenuation of NO-diffusion into platelets and the lowering of cGMP biosynthesis