. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science. 2009 Apr 3;324(5923):102-5. PubMed.


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  1. To explore the mechanisms underlying nitric oxide- and Aβ-induced mitochondrial fragmentation in neurons (Barsoum et al., 2006), Stuart Lipton’s group convincingly demonstrates that NO induces S-nitrosylation of Drp1 at Cys644 that enhances Drp1 dimerization and increases GTPase activity, thus leading to excessive mitochondrial fission. This study adds one additional layer, in addition to phosphorylation, sumoylation and ubiquitination, to the post-transcriptional modification and regulation of Drp1. The presence of S-nitrosylated Drp1 in Aβ25-35 treated neurons implicates a similar mechanism that likely contributes to Aβ-induced mitochondrial fragmentation. Indeed, that Drp1(C644A) expression abrogates the adverse effects of naturally secreted Aβ on spine density indirectly supports such a notion.

    Most importantly, the presence of S-nitrosylated Drp1 in Tg2576 and AD brain tissues lends pathophysiological significance to this mechanism in vivo. Overall, the work presented supports the notion that abnormal mitochondrial dynamics play a critical role in mitochondrial dysfunction and neuronal injury in AD brain, and it sheds new light on the mechanisms underlying mitochondrial dysfunction and its relation to synaptic dysfunction. Given that abnormal mitochondrial fission and fusion are increasingly implicated in other neurodegenerative diseases such as Parkinson's and Huntington's (Frank et al., 2001; Lee et al., 2004; Chen et al., 2005; McBride et al., 2006; Parone et al., 2006; Yu et al., 2006; Lee et al., 2007), it would be of interest to see whether similar mechanisms also play a role in those diseases.

    Both mitochondrial dysfunction and synaptic dysfunction are early events during AD pathogenesis; however, whether and how the former affects the latter was unclear. Recently we demonstrated that Aβ overproduction causes both mitochondrial fragmentation and abnormal distribution in neuronal cells (Wang et al., 2008). We also demonstrated that excessive fragmentation compromised mitochondrial function. This, together with an abnormal distribution, likely contributes to synaptic dysfunction. Although we demonstrated that an imbalance in the mitochondrial fission and fusion machinery was directly responsible for Aβ-induced mitochondrial fragmentation, the present study offers another mechanism through enhanced S-nitrosylation of Drp1. In vivo, it is likely that both mechanisms may be in play.

    Nonetheless, since enhanced mitochondrial fission does not necessarily cause synaptic dysfunction (Li et al., 2004), it remains to be determined whether and how Drp1(C644A) affects mitochondrial function and distribution and thus abrogated the adverse effect of naturally secreted Aβ on spine density.


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