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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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“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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“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.”
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“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).”
BackgroundNeuronal calcium signaling: function and dysfunction
Brini, M., Calí, T., Ottolini, D., & Carafoli, E. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1550-7 · Cited by 790
“[167] and in mitochondria in HD model cells [159].”
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“Some evidence suggests that mutant huntingtin can interact with the outer mitochondrial membrane resulting in mitochondrial calcium abnormalities (Panov et al. 2002)(Choo et al. 2004).”
Mechanisms of neurodegeneration in Huntington’s disease
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“effect that was accompanied by a significant release of cytochrome c (Choo et al., 2004).”
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N-Terminal Mutant Huntingtin Associates with Mitochondria and Impairs Mitochondrial Trafficking
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“Although increasing evidence indicates that mutant htt can affect mitochondria directly in vitro (Panov et al., 2002; Choo et al., 2004; Rockabrand et al., 2007), it remains unclear whether full-length mutant htt or its proteolytic fragments have a direct effect on mitochondria in vivo.”
BackgroundMethodInfluentialFerroptosis Mechanisms Involved in Neurodegenerative Diseases
Reichert, C. O., de Freitas, F. A., Sampaio‐Silva, J., Rokita-Rosa, L., Barros, P. D. L., Levy, D., & Bydlowski, S. P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228765 · Cited by 431
“It has been shown that mHTT and the wild version are associated with the outer mitochondrial membrane [224].”
BackgroundMitochondrial Diseases of the Brain
Chaturvedi, R. K., & Beal, M. F. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.03.018 · Cited by 426
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Huntington's disease: from pathology and genetics to potential therapies
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BackgroundParkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation
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Self-citationShirendeb, U. P., Calkins, M. J., Mańczak, M., Anekonda, V., Dufour, B. D., McBride, J. L., Mao, P., & Reddy, P. H. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr475 · Cited by 402
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“In line with these findings, Choo et al. (2004) demonstrated that Htt is associated with outer mitochondrial membranes and that the mutated form of the protein is able to promote mitochondrial permeability transition as well as a decrease in the Ca2+ threshold necessary to induce it.”
ResultDisturbed Ca 2+ signaling and apoptosis of medium spiny neurons in Huntington's disease
Tang, T.-S., Slow, E., Lupu, V. D., Stavrovskaya, I. G., Sugimori, M., Llinás, R., Kristal, B. S., Hayden, M. R., & Борисович, Б. И. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409402102 · Cited by 360
Calcium signaling in neurodegeneration
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Protein Quality Control by Molecular Chaperones in Neurodegeneration
Ciechanover, A. J., & Kwon, Y. T. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00185 · Cited by 366
“…of Hsp70 proteins include mutant huntingtin (mHTT) in HD and other polyQ diseases, α-synuclein in PD, amyloid-β (Aβ) and hyperphosphorylated tau in AD, and mutant SOD1 in ALS (Choo et al., 2004; Dedmon et al., 2005; Liu et al., 2005; Evans et al., 2006; Dompierre et al., 2007; Luk et al., 2008).”
BackgroundManczak, M., & Reddy, P. H. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds360 · Cited by 348
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Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity
Subramaniam, S., Sixt, K. M., Barrow, R. K., & Snyder, S. H. (2009) · Science · doi:10.1126/science.1172871 · Cited by 347
Giorgi, C., Missiroli, S., Patergnani, S., Duszyński, J., Wieckowski, M. R., & Pinton, P. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6223 · Cited by 343
“8) (27).”
Mitochondrial association of alpha-synuclein causes oxidative stress
Parihar, M. S., Parihar, A., Fujita, M., Hashimoto, M., & Ghafourifar, P. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-7589-1 · Cited by 340
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Celsi, F., Pizzo, P., Brini, M., Leo, S., Fotino, C., Pinton, P., & Rizzuto, R. (2009) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2009.02.021 · Cited by 335
“showed that mutated, but not wild type, Htt induces PTP opening in isolated mitochondria [88], and we recently demonstrated a facilitated opening of PTP in permeabilized polyQ-Htt expressing cells [89].”
BackgroundOxidative Damage in Huntington's Disease Pathogenesis
Browne, S. E., & Beal, M. F. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.8.2061 · Cited by 313
Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons
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Mitochondrial Approaches for Neuroprotection
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HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism
Seong, I. S., Ivanova, E. V., Lee, J., Choo, Y. S., Fossale, E., Anderson, M., Gusella, J. F., Laramie, J. M., Myers, R. H., Lesort, M. J., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi319 · Cited by 291
“Mitochondria were isolated according to a procedure described previously (39) and suspended in buffer A (5 mM HEPES, 3 mM MgCl2, 1 mM EGTA, 250 mM sucrose, pH 7.”
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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…”
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“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
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“For immunoprecipitation, 300 g of mitochondrial and cytosolic proteins was used (53, 54).”
MethodMitochondria in Huntington's disease
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“One important point is that mutant Htt can interact with the outer mitochondrial membrane [50-53].”
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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).”
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BackgroundDopaminergic Signaling and Striatal Neurodegeneration in Huntington's Disease
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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 210
“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
“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
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“…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 194
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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
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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
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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 166
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
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 162
“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 164
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
“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
Agrawal, S., Fox, J. A., Thyagarajan, B., & Fox, J. H. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.04.002 · Cited by 155
“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
“…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 155
“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
“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 164
“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 153
“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 154
Cherubini, M., López-Molina, L., & Ginés, S. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104741 · Cited by 148
“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 153
“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 149
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
“, 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 147
“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 144
“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
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
“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
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 145
“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 145
“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
“(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 142
“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
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
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