Cited by 515Genetic Neurodegenerative DiseasesMitochondrial Function and PathologyParkinson's Disease Mechanisms and Treatments

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Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release

Choo, Y. S.·2004·Human Molecular Genetics

DOI 10.1093/hmg/ddh162

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Abstract

Huntington's disease (HD) is initiated by an abnormally expanded polyglutamine stretch in the huntingtin protein, conferring a novel property on the protein that leads to the loss of striatal neurons. Defects in mitochondrial function have been implicated in the pathogenesis of HD. Here, we have examined the hypothesis that the mutant huntingtin protein may directly interact with the mitochondrion and affect its function. In human neuroblastoma cells and clonal striatal cells established from HdhQ7 (wild-type) and HdhQ111 (mutant) homozygote mouse knock-in embryos, huntingtin was present in a purified mitochondrial fraction. Subfractionation of the mitochondria and limited trypsin digestion of the organelle demonstrated that huntingtin was associated with the outer mitochondrial membrane. We further demonstrated that a recombinant truncated mutant huntingtin protein, but not a wild-type, directly induced mitochondrial permeability transition (MPT) pore opening in isolated mouse liver mitochondria, an effect that was prevented completely by cyclosporin A (CSA) and ATP. Importantly, the mutant huntingtin protein significantly decreased the Ca2+ threshold necessary to trigger MPT pore opening. We found a similar increased susceptibility to the calcium-induced MPT in liver mitochondria isolated from a knock-in HD mouse model. The mutant huntingtin protein-induced MPT pore opening was accompanied by a significant release of cytochrome c, an effect completely inhibited by CSA. These findings suggest that the development of specific MPT inhibitors may be an interesting therapeutic avenue to delay the onset of HD.

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“These cell lines show an association of huntingtin with the outer mitochondrial membrane.(77) Alternatively alterations in gene transcription may contribute mitochondrial dysfunction in HD.”
Background
Molecular Mechanisms and Potential Therapeutical Targets in Huntington's Disease
Zuccato, C., Valenza, M., & Cattaneo, E. (2010) · Physiological Reviews · doi:10.1152/physrev.00041.2009 · Cited by 848
“It was suggested that mitochondrial calcium handling defects may be partly due to a direct deleterious effect of mutant huntingtin on the outer mitochondrial membrane, since incubation of normal mitochondria with the mutant protein reproduced the calcium-handling defect seen in human HD mitochondria (116, 426, 427).”
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Authors: Choo, Y. S.
Affiliations: University of Alabama at Birmingham (US)
Corresponding author: Choo, Y. S.
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2004-05-05
Volume: 13
Issue: 14
Pages: 1407-1420
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/ddh162
OpenAlex: W2100103422
Cited by: 515
References: 56
Citations by year: 2026: 12 · 2025: 16 · 2024: 14 · 2023: 22 · 2022: 28 · 2021: 34 · 2020: 27 · 2019: 21 · 2018: 24 · 2017: 19 · 2016: 21 · 2015: 23 · 2014: 27 · 2013: 17 · 2012: 35
FWCI: 9.16
Type: journal article
Language: en
Open access: closed
Locations: Human Molecular Genetics (publishedVersion)
PubMed (publishedVersion)
HighWire Press Open Archive (submittedVersion)
Funders: Hereditary Disease Foundation
National Institute of Neurological Disorders and Stroke (R01NS041552, R01NS041744, NS32765, NS41744, R01NS032765, NS41552)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords: mutant huntingtin, Huntington's disease, mitochondrial permeability transition, cytochrome c release, cyclosporine, mitochondrial outer membrane, polyglutamine expansion, striatal neurons
MeSH terms: Huntingtin Protein, Mitochondrial Permeability Transition Pore, Adenosine Triphosphate, Animals, Calcium, Cell Line, Humans, Huntington Disease, Intracellular Membranes, Ion Channels, Mitochondria, Liver, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Recombinant Proteins, Cyclosporine, Mitochondrial Membrane Transport Proteins, Cytochromes c, Serotonin Plasma Membrane Transport Proteins, Mice

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Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release

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