S-Nitrosylation of Drp1 Mediates β-Amyloid-Related Mitochondrial Fission and Neuronal Injury

• DOI: 10.1126/science.1171091
• Publication Date: 2009-04-02T21:36:39Z
• Authors: Dong-Hyung Cho; Tomohiro Nakamura; Jianguo Fang; Piotr Cieplak; Adam Godzik; Zezong Gu; Stuart A. Lipton
• Keywords: Cerebral Cortex; Dynamins; Male; Models, Molecular; 0303 health sciences; Amyloid beta-Peptides; Amino Acid Motifs; Mice, Transgenic; Cell Line; GTP Phosphohydrolases; Mitochondria; 3. Good health; Mitochondrial Proteins; Mice; 03 medical and health sciences; Alzheimer Disease; Cell Line, Tumor; Mutation; Animals; Humans; Female; Cysteine; Microtubule-Associated Proteins

Mitochondria continuously undergo two opposing processes, fission and fusion. The disruption of this dynamic equilibrium may herald cell injury or death and may contribute to developmental and neurodegenerative disorders. Nitric oxide functions as a signaling molecule, but in excess it mediates neuronal injury, in part via mitochondrial fission or fragmentation. However, the underlying mechanism for nitric oxide–induced pathological fission remains unclear. We found that nitric oxide produced in response to β-amyloid protein, thought to be a key mediator of Alzheimer's disease, triggered mitochondrial fission, synaptic loss, and neuronal damage, in part via S-nitrosylation of dynamin-related protein 1 (forming SNO-Drp1). Preventing nitrosylation of Drp1 by cysteine mutation abrogated these neurotoxic events. SNO-Drp1 is increased in brains of human Alzheimer's disease patients and may thus contribute to the pathogenesis of neurodegeneration.