Inhibition of mitochondrial protein import by mutant huntingtin

Yano, Hiroko; Баранов, С. В.; Baranova, Oxana V.; Kim, Jin-Ho; Pan, Yanchun; Yablonska, Svitlana; Carlisle, Diane L.; Ferrante, Robert J.; Kim, Albert H.; Friedlander, Robert M.

doi:10.1038/nn.3721

Cited by 189 publications

(213 citation statements)

References 53 publications

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“…It was recently shown that mitochondrial protein import is inhibited by mHtt leading to neuronal death [97]. Here we show that mitochondrial levels of Tom20 and Tom40 are significantly enhanced by insulin in HD striatal cells, suggesting that the peptide may promote increased recognition, movement and import of cytosolically synthesized mitochondrial proteins.…”

Section: Discussionmentioning

confidence: 52%

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

Ribeiro

Rosenstock

Oliveira

et al. 2014

Free Radical Biology and Medicine

120

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Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington's disease knock-in striatal cells, Free Radical Biology and Medicine, http://dx.doi.org/10.1016/j. freeradbiomed.2014.06.023 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Discussionmentioning

confidence: 52%

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

Ribeiro

Rosenstock

Oliveira

et al. 2014

Free Radical Biology and Medicine

120

View full text Add to dashboard Cite

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“…It was recently reported that mHtt inhibits protein import into mitochondria in vitro (isolated mouse forebrain mitochondria and HdhQ111 striatal cell line) and in vivo (R6/2 mice) (Jonas, 2014;Yano et al, 2014). Using immunoprecipitation and TIM23 overexpression experiments, the authors suggest that mitochondrial protein import is inhibited by the direct interaction of mHtt with the TIM23 complex (Yano et al, 2014) (Fig.…”

Section: Mitochondrial Biogenesismentioning

confidence: 98%

“…Using immunoprecipitation and TIM23 overexpression experiments, the authors suggest that mitochondrial protein import is inhibited by the direct interaction of mHtt with the TIM23 complex (Yano et al, 2014) (Fig. 1B).…”

Section: Mitochondrial Biogenesismentioning

confidence: 99%

Mitochondrial dynamics and quality control in Huntington's disease

Guedes-Dias

Pinho

Soares

et al. 2016

Neurobiology of Disease

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Huntington's disease (HD) is an inherited neurodegenerative disorder caused by polyglutamine expansion mutations in the huntingtin protein. Despite its ubiquitous distribution, expression of mutant huntingtin (mHtt) is particularly detrimental to medium spiny neurons within the striatum. Mitochondrial dysfunction has been associated with HD pathogenesis. Here we review the current evidence for mHtt-induced abnormalities in mitochondrial dynamics and quality control, with a particular focus on brain and neuronal data pertaining to striatal vulnerability. We address mHtt effects on mitochondrial biogenesis, protein import, complex assembly, fission and fusion, mitochondrial transport, and on the degradation of damaged mitochondria via autophagy (mitophagy). For an integrated perspective on potentially converging pathogenic mechanisms, we also address impaired autophagosomal transport and abnormal mHtt proteostasis in HD.

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“…Although the functional relationship of Htt to mitochondria is still uncertain [21], it is becoming increasingly apparent that mHtt can impair mitochondrial function directly [22]. Moreover, available data indicate that mitochondrial defects may initiate the disease onset [23][24][25][26][27][28][29][30][31].…”

Section: Huntington's Diseasementioning

confidence: 99%

VDAC as a Potential Target in Huntingtons Disease Therapy: The State of the Art

Karachitos¹,

Grobys²

2015

Pharmaceut Reg Affairs

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It is becoming increasingly evident that mitochondria dysfunction plays an important role in pathogenesis of Huntington's disease (HD). However, the underlying mechanism is still needs to be explained. The crucial aspect of the explanation is to indicate the upstream events in mitochondria dysfunction that could contribute to HD. In the review we propose the defect of voltage-dependent anion-selective channel (VDAC), as a causative event in HDrelated mitochondria dysfunction. Thus, we propose to consider VDAC as a crucial element in HD etiology and consequently as a reasonable target for therapeutic interventions in HD, based on developing novel therapeutic strategies eliminating mitochondria dysfunction.Keywords: Huntington's disease; VDAC; Mitochondria; Therapy Huntington's DiseaseHuntington's disease (HD) is a progressive and fatal neurodegenerative disease with a prevalence of about 5-10/100 000. Clinically, the disease is characterized by progressive chorea (involuntary dance-like movements), rigidity, weight loss, dementia, seizures and psychiatric disturbances such as depression, withdrawal and irritability. These symptoms including cognitive deterioration, psychiatric disturbances, and movement disorders result from a selective and continuous loss of neurons from the striatum and deep layers of the cerebral cortex although other brain regions such as thalamus and subthalamic nucleus are also affected [1][2][3]. Current treatments for HD relieve merely the symptoms and address the control of behavioral symptoms, motor sedatives, cognitive enhancers, and neuroprotective agents [4,5] but are not able to restore neuronal function nor to stop the insidious loss of neurons. As summarized by Kumar et al. [6], although there is an intensive research concerning development of neuroprotective strategies such as fetal neural transplantation, RNA interference (RNAi) and transglutaminase inhibitors (TGaseI), effective therapeutic strategies may not be developed until the next few decades. Thus, a new therapeutic approach involving new potential targets and to start before the symptomatic stage could contribute to HD treatment to be more specific and effective. This, in turn, requires further studies concerning molecular mechanisms underlying HD.The genetic hallmark of HD is an expansion of an unstable trinucleotide CAG repeat region within the first exon of the gene encoding the protein Huntington (Htt). This results in synthesis of its mutant form (mHtt) containing more than 36 glutamine residues at N terminus although the possible contribution of mHtt encoding mRNA, i.e. toxic mRNA in HD etiology has also been suggested [7]. HD inheritance is autosomal dominant and consequently the prevailing view is that mHtt mediated symptoms result from a toxic gain-offunction mechanism although loss-of-function mechanisms for mHtt and Htt are also proposed [8,9]. Htt is conserved among vertebrates [10], is localized mainly in cytoplasm and exhibits anti-apopptotic properties [11,12]. Importantly, Htt expression in diffe...

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Inhibition of mitochondrial protein import by mutant huntingtin

Cited by 189 publications

References 53 publications

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

Mitochondrial dynamics and quality control in Huntington's disease

VDAC as a Potential Target in Huntingtons Disease Therapy: The State of the Art

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