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

By D. Cho, Tomohiro Nakamura, Jianguo Fang, P. Cieplak, Adam Godzik, Z. Gu, S. Lipton. Science, 2009

1,067 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Nutrition and Dietetics, Physiology

View Paper: https://www.semanticscholar.org/paper/d354baf2ad0da747db29ce1f9ab8134459554eba

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Citations in the corpus

• The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice (2009, background): “Abnormalities in division have also been implicated in Charcot-Marie-Tooth type 4A, Parkinson’s disease, Alzheimer’s disease, and abnormal brain development (Cuesta et al., 2002; Waterham et al., 2007; Deng et al., 2008; Poole et al., 2008; Yang et al., 2008; Cho et al., 2009).”
• Mitochondrial Dysfunction in Neurodegenerative Diseases (2012, background): “Several studies have reported impaired mitochondrial dynamics that involve the abnormal expression of Drp1 in postmortem brains from patients with AD, AD mouse models, and APP cell lines (Cho et al., 2009; reviewed in Reddy et al., 2011).”
• Role of ROS and RNS Sources in Physiological and Pathological Conditions (2016, background): “This consequence can be observed as cognitive deficits as NF𝜅-B is generated and neuroinflammation occurs.”
• The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. (2012, positive): “…of necrotic cell death (also known as necroptosis) has been implicated in development , tissue damage during acute pancreatitis, retinal detachment , and antiviral immunity (Cho et al., 2009b; He et al., 2009; Kaiser et al., 2011; Oberst et al., 2011; Trichonas et al., 2010; Upton et al., 2010).”
• Synaptic energy use and supply. (2012, background): “, 2009), in part as a result of nitric oxide produced in response to the amyloid b (Ab) that is a hallmark of AD (Cho et al., 2009).”
• Mechanisms of mitochondrial fission and fusion. (2013, background): “Another membrane-bound E3 ligase, Mulan or Mapl, was proposed to regulate Drp1 through sumoylation (Braschi et al. 2009), and NO-dependent nitrosylation of a Drp1 has been proposed to activate fission in a way that promotes neurodegeneration in Alzheimer’s patients (Cho et al. 2009).”