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.
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Mutant Htt associates directly with the outer mitochondrial membrane.
“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]
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“It has been reported that the multiple changes in mitochondrial Ca2þ handling (Panov et al, 2002), metabolism (Damiano et al, 2010), and susceptibility to apoptosis (Sawa et al, 1999) could be related to mitochondrial localization of mutated Htt (Orr et al, 2008) or to transcriptional regulation of the master mitochon…”
BackgroundInfluentialRockabrand, E., Slepko, N., Pantalone, A., Nukala, V. N., Kazantsev, A. G., Marsh, J., Sullivan, P. G., Steffan, J. S., Sensi, S. L., & Thompson, L. M. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl440 · Cited by 288 · see citing works
“The Htt protein, either endogenous or exogenous full-length or N-terminal fragments, can associate with mitochondria (29,33,34), and in particular can co-fractionate with the outer mitochondrial membrane (32).”
BackgroundBNIP3 Protein Suppresses PINK1 Kinase Proteolytic Cleavage to Promote Mitophagy
Zhang, T., Xue, L., Li, L., Tang, C., Wan, Z., Wang, R., Tan, J., Tan, Y., Han, H., Tian, R., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.733410 · Cited by 285 · see citing works
“For immunoprecipitation, 300 g of mitochondrial and cytosolic proteins was used (53, 54).”
MethodMitochondria in Huntington's disease
Damiano, M. G., Galvan, L., Déglon, N., & Brouillet, E. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.07.012 · Cited by 282 · see citing works
“One important point is that mutant Htt can interact with the outer mitochondrial membrane [50-53].”
BackgroundInfluentialExploring the Role of Neuroplasticity in Development, Aging, and Neurodegeneration
Marzola, P., Melzer, T., Pavesi, E., Gil-Mohapel, J., & Brocardo, P. S. (2023) · Brain Sciences · doi:10.3390/brainsci13121610 · Cited by 281 · see citing works
“For example, mutant huntingtin has been shown to disrupt mitochondrial function and dynamics in HD [279].”
BackgroundMutant huntingtin and mitochondrial dysfunction
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“Mitochondria isolated from cell expressing mutated Htt show decreased membrane potential, a defect in Ca2 homeostasis, and higher susceptibility to Ca2 -induced permeability transition (Panov et al., 2002; Choo et al., 2004).”
BackgroundLiot, G., Bossy, B., Lubitz, S., Kushnareva, Y., Sejbuk, N. E., & Bossy‐Wetzel, E. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.22 · Cited by 239 · see citing works
“release of cytochrome c, suggesting a direct effect of the protein on mitochondria.(10) 3-Nitropropionic acid (3-NP), an irreversible inhibitor of the”
Impaired PGC-1α function in muscle in Huntington's disease
Chaturvedi, R. K., Adhihetty, P. J., Shukla, S., Hennessy, T., Calingasan, N. Y., Yang, L., Starkov, A. A., Kiaei, M., Cannella, M., Sassone, J., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp243 · Cited by 237 · see citing works
Inhibition of mitochondrial protein import by mutant huntingtin
Yano, H., Baranov, S. V., Baranova, O. V., Kim, J., Pan, Y., Yablonska, S., Carlisle, D. L., Ferrante, R. J., Kim, A. H., & Friedlander, R. M. (2014) · Nature Neuroscience · doi:10.1038/nn.3721 · Cited by 226 · see citing works
Huntington’s disease: from huntingtin function and dysfunction to therapeutic strategies
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PGC-1α, mitochondrial dysfunction, and Huntington's disease
Johri, A., Chandra, A., & Beal, M. F. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.04.016 · Cited by 223 · see citing works
Energy deficit in Huntington disease: why it matters
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Excitotoxic Neuronal Death and the Pathogenesis of Huntington's Disease
Estrada‐Sánchez, A. M., Mejía-Toiber, J., & Massieu, L. (2008) · Archives of Medical Research · doi:10.1016/j.arcmed.2007.11.011 · Cited by 213 · see citing works
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“Studies with purified mitochondria demonstrated that mutant huntingtin can associate with the outer mitochondrial membrane and directly induce the opening of the mitochondrial permeability transition pore with simultaneous release of cytochrome C.(117) In addition, deficits of mitochondrial complexes I, II, and IV hav…”
BackgroundDopaminergic Signaling and Striatal Neurodegeneration in Huntington's Disease
Tang, T.-S., Chen, X., Liu, J., & Борисович, Б. И. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.1396-07.2007 · Cited by 207 · see citing works
Mitochondrial Dysfunction in Huntington’s Disease
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Mitochondria in Neurodegeneration
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“HD is strictly an autosomal dominant disorder and it is caused by a CAG triplet repeat expansion (>35 CAGs) in the first exon of the Huntingtin (HTT) gene on chromosome 4 (Huntington’s Disease Collaborative Research Group, 1993).”
BackgroundInfluentialMitochondria-associated membranes as hubs for neurodegeneration
Krols, M., Isterdael, G. V., Asselbergh, B., Kremer, A., Lippens, S., Timmerman, V., & Janssens, S. (2016) · Acta Neuropathologica · doi:10.1007/s00401-015-1528-7 · Cited by 200 · see citing works
“In the context of Huntington’s disease for example, the binding of mutant huntingtin to IP3R may result in a heightened susceptibility of mitochondria to activate the permeability transition pore and the subsequent release of pro-apoptotic factors [23].”
BackgroundFerrante, R. J., Ryu, H., Kubilus, J. K., D’Mello, S. R., Sugars, K. L., Lee, J.-H., Lu, P., Smith, K., Browne, S. E., Beal, M. F., et al. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.2599-04.2004 · Cited by 195 · see citing works
“Furthermore, mutant htt has been demonstrated to be associated with the outer mitochondrial membrane, and recombinant truncated mutant htt, but not wild type, can directly induce MPT pore opening in isolated mouse liver mitochondria (Choo et al., 2004).”
BackgroundMastroberardino, P. G., Hoffman, E. K., Horowitz, M. P., Betarbet, R., Taylor, G., Cheng, D., Na, H. M., Gutekunst, C.-A., Gearing, M., Trojanowski, J. Q., et al. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.02.009 · Cited by 195 · see citing works
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Franco-Iborra, S., Vila, M., & Perier, C. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00342 · Cited by 194 · see citing works
“…directly interacting with the outer mitochondrial membrane Frontiers in Neuroscience | www.frontiersin.org 3 May 2018 | Volume 12 | Article 342 (OMM) (Gutekunst et al., 1998; Choo et al., 2004; Orr et al., 2008), reinforcing the notion that mutant huntingtin directly impairs mitochondrial function.”
BackgroundCalcium Homeostasis and Mitochondrial Dysfunction in Striatal Neurons of Huntington Disease
Lim, D., Fedrizzi, L., Tartari, M., Zuccato, C., Cattaneo, E. F., Brini, M., & Carafoli, E. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704704200 · Cited by 192 · see citing works
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Ehrnhoefer, D. E., Sutton, L. M., & Hayden, M. R. (2011) · The Neuroscientist · doi:10.1177/1073858410390378 · Cited by 184 · see citing works
Colby, D. W., Chu, Y., Cassady, J. P., Duennwald, M. L., Zazulak, H., Webster, J. M., Messer, A. C., Lindquist, S. L., Ingram, V. M., & Wittrup, K. D. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408134101 · Cited by 183 · see citing works
The role of mitochondria in inherited neurodegenerative diseases
Kwong, J. Q., Beal, M. F., & Manfredi, G. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03990.x · Cited by 180 · see citing works
Mitochondria and Huntington's Disease Pathogenesis: Insight from Genetic and Chemical Models
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Synaptic pathology: A shared mechanism in neurological disease
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Role of mitochondrial dysfunction in the pathogenesis of Huntington's disease
Quintanilla, R. A., & Johnson, G. V. W. (2009) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2009.07.010 · Cited by 173 · see citing works
The mitochondrial permeability transition in neurologic disease
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“This important study provides a crucial link between nuclear and mitochondrial events in HD. Similarly, Choo et al. (2004) showed that the mutant Htt may directly interact with the outer mitochondrial membrane and affect its functions.”
BackgroundElevated brain 3-hydroxykynurenine and quinolinate levels in Huntington disease mice
Guidetti, P., Bates, G. P., Graham, R. K., Hayden, M. R., Leavitt, B. R., MacDonald, M. E., Slow, E., Wheeler, V. C., Woodman, B., & Schwarcz, R. M. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.02.011 · Cited by 166 · see citing works
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Selective Neuronal Degeneration in Huntington's Disease
Cowan, C. M., & Raymond, L. A. (2006) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(06)75002-5 · Cited by 163 · see citing works
Interaction of Mitochondrial Calcium and ROS in Neurodegeneration
Baev, A. Y., Vinokurov, A. Y., Novikova, I. N., Dremin, V. V., Potapova, E. V., & Abramov, A. Y. (2022) · Cells · doi:10.3390/cells11040706 · Cited by 162 · see citing works
Shaping the role of mitochondria in the pathogenesis of Huntington's disease
Costa, V., & Scorrano, L. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.65 · Cited by 159 · see citing works
“Several studies on mitochondria from lymphoblasts from HD patients, mouse models brains and neuronal HD cell lines reported a reduction in mitochondrial membrane potential and an enhanced sensitivity to Ca 2 þ -induced PTP (Panov et al , 2002; Choo et al , 2004; Gizatullina et al , 2006).”
Mitochondrial structural and functional dynamics in Huntington's disease
Reddy, P. H., Mao, P., & Mańczak, M. (2009) · Brain Research Reviews · doi:10.1016/j.brainresrev.2009.04.001 · Cited by 159 · see citing works
Huntingtin-deficient zebrafish exhibit defects in iron utilization and development
Lumsden, A. L., Henshall, T. L., Dayan, S., Lardelli, M. T., & Richards, R. I. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm138 · Cited by 156 · see citing works
“Htt associates with a variety of cellular structures and organelles including the plasma membrane, clathrin-coated and non-coated vesicles, endosomes, endoplasmic reticulum, Golgi complex, mitochondria, and microtubules (31, 33, 39-44).”
The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies
Bauer, P. O., & Nukina, N. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06302.x · Cited by 178 · see citing works
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“However, huntingtin also interacts with mitochondria [27,28] such that it triggers mitochondrial fragmentation, stimulates mitophagy, and impairs mitochondrial protein import [29–32].”
Impaired GAPDH‐induced mitophagy contributes to the pathology of Huntington's disease
Hwang, S., Disatnik, M., & Mochly‐Rosen, D. (2015) · EMBO Molecular Medicine · doi:10.15252/emmm.201505256 · Cited by 153 · see citing works
“…fragmentation (Cui et al, 2006; Reddy et al, 2011) and altering a process of mitophagy (Martin et al, 2015) (Fig 7) along with impairing mitochondrial trafficking and Ca2+ buffering capacity (Choo et al, 2004; Chang et al, 2006; Orr et al, 2008), collectively contribute to the pathology of HD.”
BackgroundHuang, M., Chiang, S., Kalinowski, D. S., Bae, D.-H., Sahni, S., & Richardson, D. R. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/6392763 · Cited by 154 · see citing works
“Mitochondria from HD patient lymphoblasts or from a HD mouse model have a lower membrane potential and become depolarized at lower Ca loads than relevant controls [237, 238].”
BackgroundMitochondrial iron homeostasis and its dysfunctions in neurodegenerative disorders
Mena, N. P., Urrutia, P. J., Lourido, F., Carrasco, C. M., & Núñez, M. T. (2015) · Mitochondrion · doi:10.1016/j.mito.2015.02.001 · Cited by 154 · see citing works
“Mutant Htt-STHdhQ111 is found in the mitochondrial outer membrane in striatal cells obtained from patients with HD and from HD model transgenic mice (Choo et al., 2004; Panov et al., 2002).”
Tanaka, M., Szabó, Á., Spekker, E., Polyák, H., Tóth, F., & Vécsei, L. (2022) · Cells · doi:10.3390/cells11162607 · Cited by 159 · see citing works
“The homozygous HdhQ111 KI mutant huntingtin was found to be associated with the outer mitochondrial membrane, directly induced mitochondrial permeability transition (MPT) pore opening, and significantly decreased the Ca2+ threshold to trigger MPT pore opening [233].”
BackgroundTaurine and central nervous system disorders
Menzie, J., Pan, C., Prentice, H. M., & Wu, J. (2012) · Amino Acids · doi:10.1007/s00726-012-1382-z · Cited by 151 · see citing works
“It was reported from subfractionation that mitochondria from the knock-in HD-mouse model had Exp-Htt associated with the mitochondrial outer membrane (Choo et al. 2004).”
BackgroundSiddiqui, A., Rivera, S., Castro, M. D. R., Acevedo‐Torres, K., Rane, A., Torres‐Ramos, C. A., Nicholls, D. G., Andersen, J. K., & Ayala‐Torres, S. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.06.008 · Cited by 150 · see citing works
Cherubini, M., López-Molina, L., & Ginés, S. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104741 · Cited by 147 · see citing works
“These results prompted us to propose a new but not exclusive mechanism for mitochondrial Ca mishandling in HD, which differs from some studies previously reported (Milakovic et al., 2006; Choo et al., 2004).”
ResultHuntington’s Disease and Mitochondria
Farshbaf, M. J., & Ghaedi, K. (2017) · Neurotoxicity Research · doi:10.1007/s12640-017-9766-1 · Cited by 148 · see citing works
“Choo et al. (2004) provide the presence of the normal huntingtin in mitochondrial outer membrane.”
Role of p53 in Neurodegenerative Diseases
Chang, J. R., Ghafouri, M., Mukerjee, R., Bagashev, A., Chabrashvili, T., & Sawaya, B. E. (2011) · Neurodegenerative Diseases · doi:10.1159/000329999 · Cited by 145 · see citing works
Wu, J., Shih, H.-P., Vigont, V. A., Hrdlicka, L., Diggins, L. T., Singh, C. M., Mahoney, M. B., Chesworth, R., Shapiro, G., Zimina, O. A., et al. (2011) · Chemistry & Biology · doi:10.1016/j.chembiol.2011.04.012 · Cited by 143 · see citing works
“, 2008), and by destabilizing mitochondrial Ca handling (Choo et al., 2004; Panov et al., 2002).”
Role of oxidative DNA damage in mitochondrial dysfunction and Huntington’s disease pathogenesis
Ayala‐Peña, S. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.04.017 · Cited by 142 · see citing works
“of mutant huntingtin to brain mitochondria correlates with age and disease progression in the HdhQ150 knock-in mouse model of HD [62], and results in disruption of fast axonal transport [63, 64], mitochondrial trafficking [57, 62] and calcium homeostasis [60, 65] and in reduction of mitochondrial ATP generation in syn…”
BackgroundThe Clinical and Genetic Features of Huntington Disease
Sturrock, A., & Leavitt, B. R. (2010) · Journal of Geriatric Psychiatry and Neurology · doi:10.1177/0891988710383573 · Cited by 142 · see citing works
“The direct binding of expanded huntingtin protein to the outer mitochondrial membrane has been demonstrated and may directly stimulate mPT pore opening.(108,109) Overall, a significant amount of evidence supports excitotoxicity and mitochondrial dysfunction as integral pathogenic mechanisms in HD.”
BackgroundMechanisms of protein toxicity in neurodegenerative diseases
Chung, C. G., Lee, H., & Lee, S. B. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2854-4 · Cited by 142 · see citing works
Old Things New View: Ascorbic Acid Protects the Brain in Neurodegenerative Disorders
Covarrubias‐Pinto, A., Acuña, A. I., Beltrán, F. A., Torres-Díaz, L., & Castro, M. A. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161226095 · Cited by 140 · see citing works
“Htt aggregates near mitochondria have been observed, suggesting N-terminal interaction with the outer mitochondrial membrane [247–249].”
BackgroundMutant Huntingtin Expression Induces Mitochondrial Calcium Handling Defects in Clonal Striatal Cells
Milakovic, T., Quintanilla, R. A., & Johnson, G. V. W. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m603845200 · Cited by 142 · see citing works
Oliveira, J. M. A., Chen, S., Almeida, S., Riley, R. R., Gonçalves, J., Oliveira, C. R., Hayden, M. R., Nicholls, D. G., Ellerby, L., & Rego, A. C. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.3004-06.2006 · Cited by 140 · see citing works
“Although some studies addressed the relationship between Ca 2 and m using isolated mitochondria from HD cells (Panov et al., 2002; Choo et al., 2004; Brustovetsky et al., 2005), so”
BackgroundMethodRibeiro, M., Rosenstock, T. R., Oliveira, A. M., Oliveira, C. R., & Rego, A. C. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.06.023 · Cited by 139 · see citing works
“Interaction of mHtt with the outer mitochondrial membrane was further demonstrated in mitochondria from YAC72 transgenic mice, STHdh striatal cells and in mouse liver mitochondria, causing the opening of the mitochondrial permeability transition pore [21,25].”
BackgroundMitochondria targeted therapeutic approaches in Parkinson's and Huntington's diseases
Chaturvedi, R. K., & Beal, M. F. (2012) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2012.11.011 · Cited by 139 · see citing works
“(Choo et al., 2004; Orr et al., 2008; Panov et al., 2002)”
BackgroundRoles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases
Weng, T.-Y., Tsai, S., & Su, T. (2017) · Journal of Biomedical Science · doi:10.1186/s12929-017-0380-6 · Cited by 139 · see citing works
“Mutant Htt protein induced mitochondrial permeability transition (MPT) accompanied by a significant release of cytochrome c [145].”
BackgroundOliveira, J. M. A., Jekabsons, M. B., Chen, S., Lin, A., Rego, A. C., Gonçalves, J., Ellerby, L., & Nicholls, D. G. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04361.x · Cited by 136 · see citing works
- 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 › 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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