Abstract
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 beta-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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Amino Acid Motifs
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Peptides / pharmacology
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Animals
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Cell Line
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Cell Line, Tumor
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Cerebral Cortex / cytology
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Cysteine / analogs & derivatives
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Cysteine / genetics
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Cysteine / metabolism
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Cysteine / pharmacology
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Dynamins
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Female
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GTP Phosphohydrolases / chemistry
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GTP Phosphohydrolases / metabolism*
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Humans
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Male
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Mice
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Mice, Transgenic
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Microtubule-Associated Proteins / chemistry
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Microtubule-Associated Proteins / metabolism*
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Mitochondria / drug effects
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Mitochondria / physiology
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Mitochondria / ultrastructure*
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Mitochondrial Proteins / chemistry
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Mitochondrial Proteins / metabolism*
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Models, Molecular
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Mutation
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Neurons / drug effects
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Neurons / ultrastructure*
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Nitric Oxide / metabolism*
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Peptide Fragments / metabolism
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Peptide Fragments / pharmacology
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Protein Multimerization
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Protein Structure, Tertiary
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S-Nitrosothiols / pharmacology
Substances
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Amyloid beta-Peptides
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Microtubule-Associated Proteins
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Mitochondrial Proteins
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Peptide Fragments
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S-Nitrosothiols
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amyloid beta-protein (25-35)
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Nitric Oxide
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S-nitrosocysteine
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GTP Phosphohydrolases
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DNM1L protein, human
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Dynamins
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Cysteine