The DOI matches its Crossref record; 55 of the 56 references it cites were found in a registry or an index.
Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“There is evidence from an HD mouse model, and from cultured HD striatal cells (STHdhQ111), that mutant Htt associates directly with the outer mitochondrial membrane49, 57.”
From Mitochondrial Approaches for Neuroprotection (2008) · cites this paper as [57]
Citations
Cites
Green, D. R., & Reed, J. C. (1998) · Science · doi:10.1126/science.281.5381.1309 · Cited by 9,051
MACDONALD, M. (1993) · Cell · doi:10.1016/0092-8674(93)90585-e · Cited by 8,366
(1978) · Biochemical Education · doi:10.1016/0307-4412(78)90049-3 · Cited by 5,073
Mitochondrial control of cell death
Kroemer, G., & Reed, J. C. (2000) · Nature Medicine · doi:10.1038/74994 · Cited by 3,103
The mitochondrial permeability transition pore and its role in cell death
CROMPTON, M. (1999) · Biochemical Journal · doi:10.1042/bj3410233 · Cited by 2,432
Neuropathological Classification of Huntingtonʼs Disease
VONSATTEL, J.-P., MYERS, R. H., STEVENS, T. J., FERRANTE, R. J., BIRD, E. D., & RICHARDSON, E. P. (1985) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-198511000-00003 · Cited by 2,227
Bax directly induces release of cytochrome c from isolated mitochondria
Jürgensmeier, J. M., Xie, Z., Deveraux, Q. L., Ellerby, L., Bredesen, D. E., & Reed, J. C. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.9.4997 · Cited by 1,523
Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila
Steffan, J. S., Bodai, L., Pallos, J., Poelman, M., McCampbell, A., Apostol, B. L., Kazantsev, A., Schmidt, E., Zhu, Y.-Z., Greenwald, M., et al. (2001) · Nature · doi:10.1038/35099568 · Cited by 1,228
Nucifora, F. C., Sasaki, M., Peters, M. F., Huang, H., Cooper, J. K., Yamada, M., Takahashi, H., Tsuji, S., Troncoso, J. C., Dawson, V. L., et al. (2001) · Science · doi:10.1126/science.1056784 · Cited by 1,112
Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines
Panov, A. V., Gutekunst, C.-A., Leavitt, B. R., Hayden, M. R., Burke, J. R., Strittmatter, W. J., & Greenamyre, J. T. (2002) · Nature Neuroscience · doi:10.1038/nn884 · Cited by 1,030
Cited by
Sorted by citations
Items 501–515 of 515
Application of brain organoids in Huntington's disease
Gnanarajan, R., Ravichandran, N., Karuppusamy, P. A., Uvarajan, D., & Narayanasamy, A. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-29898-1.00001-0
Étude de l'implication potentielle des marqueurs du striatum dans la maladie de Huntington
Galvan, L. (2011) · theses.fr (ABES) · doi:10.70675/ebf9c275z3ce2z474dz8d5az68c2c35df509
Khalil, B. (2016) · theses.fr (ABES) · doi:10.70675/4446111fz4182z4737zae76z7f117887a893
A Study of Striatal Markers as Disease Modifiers in Huntington's Disease
Francelle, L. (2014) · theses.fr (ABES) · doi:10.70675/ac372f63z7712z4632z8782z6b71a643add2
Développement de l’imagerie métabolique par IRM-CEST : application à la maladie de Huntington
Pépin, J. (2018) · theses.fr (ABES) · doi:10.70675/36f26e42z6133z47dbz84a3z07fae7850aa0
Reconstitution du réseau corticostriatal et cible thérapeutique dans la maladie de Huntington
Virlogeux, A. (2018) · theses.fr (ABES) · doi:10.70675/92b9e042zfafcz42e8z890bz6c7ca43e2613
Abjean, L. (2019) · theses.fr (ABES) · doi:10.70675/f664e003zf93fz467eza6a3z3d953eaffe4e
“…(Adénosine triphosphate) intracellulaires, IN TR O D U C TI O N : L a m al ad ie d e H u n ti n gt o n 24 une augmentation de la production des espèces réactives de l’oxygène (ROS) ainsi qu’un défaut de la signalisation calcique (Panov et al., 2002; Choo et al., 2004; Mochel and Haller, 2011).”
Backgroundde Longprez, L. (2018) · theses.fr (ABES) · doi:10.70675/9c720f01z8077z49d5z9df8z8e7cc0c69a1a
Developmental neurotoxicity of short-chain phthalates in human neurospheres
Jung, S., Quah, Y., Jeong, J.-S., Kim, S., Ham, O., Jung, T.-Y., Lee, H., Lee, S.-J., & Yu, W. (2026) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2026.105100
Targeting mitochondria for the treatment of neurodegenerative diseases
Li, Q., & You, M. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1835506
“Calcium dysregulation and excitotoxicity provide another major axis of mitochondrial dysfunction in HD. Mitochondria derived from HD neurons display increased sensitivity to calcium, undergoing rapid depolarization in response to calcium challenge (Choo et al., 2004).”
InfluentialIslam, M. S., Islam, M. T., Mondol, M., Islam, I., Fuad, K. M., Abid, M. F., Tajim, S., & Ferdous, R. (2026) · Advances in Redox Research · doi:10.1016/j.arres.2026.100196
Zayed, M., Mahmoud, M., Massoud, A., Darwish, R. T., & Jeong, B. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-06219-7 · Cited by 1
“Mutant huntingtin impairs mitochondrial function by disrupting the electron transport chain, inhibiting complex II activity, and interfering with mitochondrial calcium handling [111, 112].”
Sarath, A. M., Singh, N. T., Sahu, B. S., & Singh, M. D. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.154630
Pfister, E. L. (2012) · The Journal of the American Medical Association (JAMA) Network (American Medical Association) · doi:10.13028/a5gf-1e13
Metadata
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
