Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA.
Nature medicine (Impact Factor: 27.36). 02/2011; 17(3):377-82. DOI: 10.1038/nm.2313
Source: PubMed


Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease onset and severity, with a longer expansion causing earlier onset. The mechanisms of mutant huntingtin-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis. Here we tested whether mutant huntingtin impairs the mitochondrial fission-fusion balance and thereby causes neuronal injury. We show that mutant huntingtin triggers mitochondrial fragmentation in rat neurons and fibroblasts of individuals with Huntington's disease in vitro and in a mouse model of Huntington's disease in vivo before the presence of neurological deficits and huntingtin aggregates. Mutant huntingtin abnormally interacts with the mitochondrial fission GTPase dynamin-related protein-1 (DRP1) in mice and humans with Huntington's disease, which, in turn, stimulates its enzymatic activity. Mutant huntingtin-mediated mitochondrial fragmentation, defects in anterograde and retrograde mitochondrial transport and neuronal cell death are all rescued by reducing DRP1 GTPase activity with the dominant-negative DRP1 K38A mutant. Thus, DRP1 might represent a new therapeutic target to combat neurodegeneration in Huntington's disease.

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    • "Mitochondria actively move from the neuronal soma to the axon and dendrites and constantly undergo repeated cycles of fusion and fission in a process regulated by the dynamin family of GTPases (guanosine triphosphatases) (Chan, 2012). However, mitochondrial fusion and fission, collectively referred to as mitochondrial dynamics, are significantly perturbed and imbalanced in HD (Shirendeb et al, 2011; Song et al, 2011), leading to accumulation of fragmented, damaged mitochondria and increased levels of oxidative stress in cells. We recently found that inhibition of excessive mitochondrial fission (but not physiological fission) by a selective inhibitor of the mitochondrial fission protein, dynamin-related protein 1 (Drp1), prevents mutant huntingtin-induced pathology in vitro and in vivo (Guo et al, 2013), suggesting that mitochondrial dynamics is a potential therapeutic target for HD. "
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    • "Interestingly, the sites of AZC-induced protein aggregation predominantly occurred adjacent to mitochondria. Mitochondrial dysfunction is thought to be a key event in some neurodegenerative diseases, and mutant huntingtin has been shown to trigger mitochondrial fragmentation by stimulating DRP1, the mitochondrial fission GTPase dynaminrelated protein-1 (Song et al., 2011). Similarly, a-synuclein causes mitochondrial fragmentation that is implicated in the pathogenesis of PD (Nakamura et al., 2011). "
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    • "For example, decreased glucose metabolism, which is suggestive of mitochondrial dysfunction, has been found in symptomatic HD patients (Jenkins et al., 1993; Antonini et al., 1996; Gu et al., 1996; Feigin et al., 2001; Shirendeb et al., 2011). There is compelling evidence that mutant Huntingtin alters mitochondrial trafficking and function (Chang et al., 2006; Cui et al., 2006; Rockabrand et al., 2007; Orr et al., 2008; Shirendeb et al., 2011; Song et al., 2011). Complex II of the mitochondrial electron transport chain appears to be particularly vulnerable in HD (Benchoua et al., 2006) and steps, which are taken to improve mitochondrial function or increase energy metabolism in animal models of HD, have proven promising in reducing the pathology caused by the genetic mutation (Chiang et al., 2012; Damiano et al 2013). "
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