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

Abstract

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.

Fig. 1

Schema of S-nitrosylated species contributing to the accumulation of aberrant proteins and neuronal damage. NMDAR hyperactivation triggers generation of NO/ROS. S-Nitrosylation of parkin (forming SNO-PARK) and PDI (forming SNO-PDI) can contribute to neuronal cell injury in part by triggering accumulation of misfolded proteins

Fig. 2

Possible mechanism whereby S-nitrosylated species contribute to excessive mitochondrial fragmentation and neuronal damage. NMDAR hyperactivation triggers generation of NO and subsequent S-nitrosylation of neuronal proteins, contributing to synaptic damage and eventually neuronal death. Soluble oligomers of Aβ oligomers, known to be a key mediator of AD pathogenesis, can facilitate neuronal NO production in both NMDAR-dependent and -independent manners. S-Nitrosylation of Drp1 (forming SNO-Drp1) can contribute to synaptic damage and neuronal cell death by triggering excessive mitochondrial fission and bioenergetic impairment