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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Available from: Geraldine Liot, Oct 03, 2015
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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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    ABSTRACT: Peroxiredoxins are ubiquitous, thiol-specific proteins that have multiple functions in stress protection, including oxidative stress. Tsa1 is the major yeast peroxiredoxin and we show that it functions as a specific antioxidant to protect against oxidative stress caused by nascent protein misfolding and aggregation. Yeast mutants lacking TSA1 are sensitive to misfolding caused by exposure to the proline analogue azetidine-2-carboxylic acid (AZC). AZC promotes protein aggregation and its toxicity to a tsa1 mutant is caused by reactive oxygen species (ROS). Generation of [rho(o)] cells lacking mitochondrial DNA rescues the tsa1 mutant AZC sensitivity indicating that mitochondria are the source of ROS. Inhibition of nascent protein synthesis with cycloheximide prevents AZC-induced protein aggregation and abrogates ROS generation confirming that aggregate formation causes ROS production. Protein aggregation is accompanied by mitochondrial fragmentation and we show that Tsa1 localizes to the sites of protein aggregation. Protein aggregates are formed adjacent to mitochondria and our data indicate that active mitochondria generate ROS. These data indicate a new role for peroxiredoxins in protecting against ROS, generated as a result of protein misfolding and aggregate formation.
    Journal of Cell Science 01/2014; 127(6). DOI:10.1242/jcs.144022 · 5.43 Impact Factor
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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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    ABSTRACT: Sleep disorders are common in neurodegenerative diseases including Huntington's disease (HD) and develop early in the disease process. Mitochondrial alterations are believed to play a critical role in the pathophysiology of neurodegenerative diseases. In the present study, we evaluated the circadian system of mice after inhibiting the mitochondrial complex II of the respiratory chain with the toxin 3-nitropropionic acid (3-NP). We found that a subset of mice treated with low doses of 3-NP exhibited severe circadian deficit in behavior. The temporal patterning of sleep behavior is also disrupted in some mice with evidence of difficulty in the initiation of sleep behavior. Using the open field test during the normal sleep phase, we found that the 3-NP treated mice were hyperactive. The molecular clockwork responsible for the generation of circadian rhythms as measured by PER2::LUCIFERASE was disrupted in a subset of mice. Within the SCN, the 3-NP treatment resulted in a reduction in daytime firing rate in the subset of mice which had a behavioral deficit. Anatomically, we confirmed that all of the treated mice showed evidence for cell loss within the striatum but we did not see evidence for gross SCN pathology. Together, the data demonstrates that chronic treatment with low doses of the mitochondrial toxin 3-NP produced circadian deficits in a subset of treated mice. This work does raise the possibility that the neural damage produced by mitochondrial dysfunction can contribute to the sleep/circadian dysfunction seen so commonly in neurodegenerative diseases.
    ASN Neuro 12/2013; 6(1). DOI:10.1042/AN20130042 · 4.02 Impact Factor
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    • "The expression of Drp1 is increased in the striatum and cortex of HD patients, which may influence mitochondrial dysfunction in HD [64, 65]. Mutant huntingtin (mtHtt) abnormally recruits Drp1 on OMM and subsequently promotes GTPase activity of Drp1, resulting in excessive mitochondrial fragmentation [66, 67]. Recent report has revealed that hyper-activation of Drp1 is mediated by S-nitrosylation, as a result of nitric oxide produced by mtHtt [68], as also found in AD. "
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    ABSTRACT: Mitochondria are essential for proper neuronal morphogenesis and functions, as they are the major source of energy for neural development. The dynamic morphology of mitochondria determines the key functions of mitochondria. Several regulatory proteins such as dynamin-related protein 1 (Drp1) are required to maintain mitochondrial morphology via a balance between continuous fusion and fission. Activity of Drp1, a key regulator in mitochondrial fission, is modulated by multiple post-translation modifications and receptor interactions. In addition, numerous researches have revealed that the regulation of Drp1 activity and mitochondrial dynamics is closely associated with several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. In this article, we concisely review the recent findings about the biological importance of Drp1-mediated mitochondrial fission in neurons under physiological and pathological conditions.
    09/2013; 22(3):149-157. DOI:10.5607/en.2013.22.3.149
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