title: Dysfunctional Mitochondrial Dynamics in the Pathophysiology of Neurodegenerative Diseases.
abstract: Mitochondrial dysfunction occurs in neurodegenerative diseases, however molecular mechanisms underlying this process remain elusive. Emerging evidence suggests that nitrosative stress, mediated by reactive nitrogen species (RNS), may play a role in mitochondrial pathology. Here, we review findings that highlight the abnormal mitochondrial morphology observed in many neurode-generative disorders including Alzheimer's, Parkinson's, and Huntington's diseases. One mechanism whereby RNS can affect mitochondrial function and thus neuronal survival occurs via protein S-nitrosylation, representing chemical reaction of a nitric oxide (NO) group with a critical cysteine thiol. In this review, we focus on the signaling pathway whereby S-nitrosylation of the mitochondrial fission protein Drp1 (dynamin-related protein 1; forming S-nitrosothiol (SNO)-Drp1) precipitates excessive mitochondrial fission or fragmentation and consequent bioenergetic compromise. Subsequently, the formation of SNO-Drp1 leads to synaptic damage and neuronal death. Thus, intervention in the SNO-Drp1 pathway may provide therapeutic benefit in neurodegenerative diseases.
authors.affiliation: Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA ; Institute of Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, Freiburg, Germany ; Spemann Graduate School of Biology and Medicine, Albert Ludwigs University Freiburg, Freiburg, Germany ; Faculty of Biology, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Haun
authors.affiliation: Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
keywords: GTPase; S-nitrosothiol; dendritic spine loss; mitochondrial dysfunction; neurodegeneration; reactive nitrogen species