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.
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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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“Moreover, mutant huntingtin fragments can directly induce the opening of the mitochondrial permeability transition pore in isolated mouse liver mitochondria, with the consequent release of cytochrome c, as well as a decrease in the calcium threshold necessary to induce it (Choo et al., 2004), favoring the hypothesis t…”
InfluentialHuntington's disease: An update of therapeutic strategies
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Tyebji, S., & Hannan, A. J. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.008 · Cited by 62
“…corticostriatal signalling, either at cell autonomous levels by disrupting gene expression levels, calcium buffering and mitochondrial function (Choo et al., 2004; Tang et al., 2005; Thomas et al., 2011), or at cell–cell interaction levels by impairing glutamate release from cortical…”
Ferroptosis and Neurodegenerative Diseases: Insights into the Regulatory Roles of SLC7A11
Wang, C., Liu, H., Xu, S., Deng, Y. L., Xu, B., Yang, T., & Liu, W. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01343-7 · Cited by 57
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Mitochondrial-dependent apoptosis in Huntington's disease human cybrids
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“Indeed,mutant huntingtin fragmentswere previously shown to directly induce the opening of the mitochondrial permeability transition pore in isolated mouse liver mitochondria, with the consequent release of cytochrome c (Choo et al., 2004) which leads to caspase cascade activation.”
Dysregulation of Neuronal Calcium Signaling via Store-Operated Channels in Huntington's Disease
Czeredys, M. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.611735 · Cited by 56
“, 2008), and disturbing mitochondrial Ca2+ handling (Panov et al., 2002; Choo et al., 2004; Oliveira et al., 2007).”
BackgroundCoelho, P., Fão, L., Mota, S. I., & Rego, A. C. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101667 · Cited by 62
Joshi, D. C., Chavan, M. B., Gurow, K., Gupta, M., Dhaliwal, J. S., & Ming, L. C. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.117827 · Cited by 62
Neuronal Ca2+dyshomeostasis in Huntington disease
Giacomello, M., Oliveros, J. C., Naranjo, J. R., & Carafoli, E. (2013) · Prion · doi:10.4161/pri.23581 · Cited by 58
“, they have a lower [Ca] threshold for the depolarization of their inner membrane and higher propensity to PTP opening.(19,20) Similar mitochondrial Ca handling defects have been also reported in clonal striatal cells expressing an Htt form carrying 111Q.”
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Mutant Huntingtin and Elusive Defects in Oxidative Metabolism and Mitochondrial Calcium Handling
Brustovetsky, N. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9188-0 · Cited by 54
“Htt65 reduced Ca threshold for PTP induction and could directly stimulate Ca-dependent PTP induction in mouse liver mitochondria [32].”
InfluentialPolyglutamine gene function and dysfunction in the ageing brain
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“Recent results argue for a direct interaction of mhtt with proteins of the mitochondrial membrane [25, 34, 62, 63] and mitochondrial raft-like micro-domains [64].”
BackgroundFukui, H., & Moraes, C. T. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm023 · Cited by 57
“Cytosolic Htt aggregates partially colocalized with mitochondria stained by Mitotracker Red, consistent with the previous finding that Htt protein can interact with the outer membrane of the mitochondria (45).”
BackgroundJung, H., Kim, S. Y., Cecen, F. S. C., Cho, Y., & Kwon, S. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.599792 · Cited by 56
Striatal specificity of gene expression dysregulation in Huntington's disease
Thomas, E. A. (2006) · Journal of Neuroscience Research · doi:10.1002/jnr.21046 · Cited by 53
“…can affect calcium signaling by enhancing inositol-(1,4,5) triphosphate-induced intracellular calcium release (Tang et al., 2003), stimulating glutamate receptor activity (Chen et al., 1999; Zeron et al., 2002) and destabilizing mitochondrial calcium balance (Panov et al., 2002; Choo et al., 2004).”
BackgroundPellman, J. J., Hamilton, J., Brustovetsky, T., & Brustovetsky, N. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13165 · Cited by 51
“In earlier studies, mitochondrial dysfunction and a decreased ability of mitochondria to accumulate Ca2+ have been proposed to contribute to HD pathogenesis (Panov et al. 2002; Choo et al. 2004; Milakovic et al. 2006).”
InfluentialAge‐related changes in regional brain mitochondria from Fischer 344 rats
LaFrance, R., Brustovetsky, N., Sherburne, C., DeLong, D., & Dubinsky, J. M. (2005) · Aging Cell · doi:10.1111/j.1474-9726.2005.00156.x · Cited by 51
Pathogenic Mechanisms in Huntington's Disease
Jones, L., & Hughes, A. (2011) · International review of neurobiology · doi:10.1016/b978-0-12-381328-2.00015-8 · Cited by 51
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“MITOCHONDRIA are involved in several neuro-degenerative diseases such as Parkinson’s disease (Abou-Sleiman et al. 2006; Keeney et al. 2006), Alzheimer’s disease (Atamna and Boyle 2006; Esposito et al. 2006), and Huntington’s disease (Choo et al. 2004; Benchoua et al. 2006).”
BackgroundHuntington’s Disease: Calcium Dyshomeostasis and Pathology Models
Kolobkova, Y. A., Vigont, V. A., Shalygin, A. V., & Kaznacheyeva, E. V. (2017) · Acta Naturae · doi:10.32607/20758251-2017-9-2-34-46 · Cited by 51
Selective basal ganglia vulnerability to energy deprivation: Experimental and clinical evidences
Tambasco, N., Romoli, M., & Calabresi, P. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.07.003 · Cited by 48
“Mutant htt, beyond directly impairing mitochondrial function, also alters the transcription of mitochondrial proteins, and promotes mitochondrial chain dysfunction during high calcium gradient loads, resulting in the reduction of calcium-threshold to start the apoptotic cascade (Choo et al., 2004; Luthi-Carter et al.,…”
Compromised mitochondrial complex II in models of Machado–Joseph disease
Laço, M., Oliveira, C. R., Paulson, H. L., & Rego, A. C. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.10.010 · Cited by 47
“PolyQ proteins also impair mitochondrial transport in neuronal processes and induce caspase activation through mitochondrial pathways [29,30,31].”
BackgroundHuntington's disease, calcium, and mitochondria
Giacomello, M., Hudec, R., & Lopreiato, R. (2011) · BioFactors · doi:10.1002/biof.162 · Cited by 49
Mitochondrial calcium signalling and neurodegenerative diseases
Britti, E., Delaspre, F., Tamarit, J., & Ros, J. (2018) · Neuronal Signaling · doi:10.1042/ns20180061 · Cited by 47
Prevention of cytosolic IAPs degradation: a potential pharmacological target in Huntington's Disease
Goffredo, D., Rigamonti, D., Zuccato, C., Tartari, M., Valenza, M., & Cattaneo, E. F. (2005) · Pharmacological Research · doi:10.1016/j.phrs.2005.01.006 · Cited by 46
New Insights into Mitochondria in Health and Diseases
Li, Y., Zhang, H., Yu, C., Dong, X., Yang, F., Wang, M., Wen, Z., Su, M., Li, B., & Yang, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25189975 · Cited by 48
“Furthermore, research has demonstrated that the balance of Ca 2+ within the mitochondria is also disrupted in these cells [61,62].”
BackgroundOcampo, A., Zambrano, A., & Barrientos, A. (2009) · The FASEB Journal · doi:10.1096/fj.09-148601 · Cited by 47
“These alterations could result from a direct binding of htt to mitochondria (17, 23).”
BackgroundNaia, L., Ferreira, I. L., Ferreiro, E. B., & Rego, A. C. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.07.122 · Cited by 49
Kim, S., Marekov, L. N., Bubber, P., Browne, S. E., Stavrovskaya, I. G., Lee, J., Steinert, P. M., Blass, J. P., Beal, M. F., Gibson, G. E., et al. (2005) · Neurochemical Research · doi:10.1007/s11064-005-8796-x · Cited by 46
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Lim, N. K.-H., Hung, L. W., Pang, T. Y., McLean, C., Liddell, J. R., Hilton, J. B. W., Li, Q.-X., White, A. R., Hannan, A. J., & Crouch, P. J. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu119 · Cited by 45
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“MPT pore formation was assessed as the degree of calcium (Ca2þ)-induced swelling and was measured spectrophotometrically (540 nm) as described previously [6,22,23].”
MethodThe Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease
Blum, D. L., Chern, Y., Domenici, M. R., Buée, L., Lin, C., Rea, W. P., Ferré, S., & Popoli, P. (2018) · Journal of Caffeine and Adenosine Research · doi:10.1089/caff.2018.0006 · Cited by 48
“mHtt found localized in the neuronal mitochondrial membrane(53) has been shown to impair mitochondrial biogenesis, fission,(54,55) axonal transport,(56) membrane potential,(53) ATP production,(57,58) and calcium handling.(53,59) Interestingly, a dysregulation of mitophagy in the mitochondria is also present in HD, and…”
BackgroundRegulation of neuronal bioenergetics as a therapeutic strategy in neurodegenerative diseases
Onyango, I. G., Bennett, J. P., & Stokin, G. B. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.303007 · Cited by 45
“All these events were completely inhibited by CsA, indicating a role for calcium and MPTP opening in the pathogenesis of this disease (Choo et al., 2004).”
BackgroundInositol 1,4,5-tripshosphate receptor, calcium signalling and huntington’s disease
Борисович, Б. И. (2007) · Springer eBooks · doi:10.1007/978-1-4020-6191-2_11 · Cited by 45
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Oliveira, A. M., Cardoso, S. M., Ribeiro, M., Seixas, R. S. G. R., Silva, A. M. S., & Rego, A. C. (2015) · Neurochemistry International · doi:10.1016/j.neuint.2015.10.004 · Cited by 44
Oliveira, J. M. A. (2010) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-010-9287-6 · Cited by 44
“However, in more concentrated suspensions (0.5 mg/ml, Panov et al. 2002; 1 mg/ml, Choo et al. 2004), Ca2+ abruptly released by a vulnerable mitochondria subset undergoing premature mPT may reach nearby mitochondria, propagating mPT across the whole population as in a nuclear chain reaction, and…”
InfluentialHuntington’s Disease and Group I Metabotropic Glutamate Receptors
Ribeiro, F. M., Pires, R. G. W., & Ferguson, S. S. G. (2010) · Molecular Neurobiology · doi:10.1007/s12035-010-8153-1 · Cited by 50
“Moreover, mutant htt protein can also cause an increase in intracellular Ca levels by destabilizing mitochondrial Ca regulation [67, 68] and sensitizing InsP3 receptor-mediated release of Ca from intracellular stores [69, 70].”
BackgroundMitochondrial matters of the brain: the role in Huntington’s disease
Turner, C., & Schapira, A. H. V. (2010) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-010-9290-y · Cited by 45
Kalathur, R. K. R., Hernández‐Prieto, M. A., & Futschik, M. E. (2012) · BMC Neurology · doi:10.1186/1471-2377-12-47 · Cited by 46
“This agrees with results of previous studies exploring mitochondrial changes due to mutant Htt in both cell culture and animal models [54,55].”
Olesoxime suppresses calpain activation and mutant huntingtin fragmentation in the BACHD rat
Clemens, L. E., Weber, J. J., Wlodkowski, T., Yu-Taeger, L., Michaud, M., Calaminus, C., Eckert, S. H., Gaca, J., Weiss, A., Magg, J. C. D., et al. (2015) · Brain · doi:10.1093/brain/awv290 · Cited by 47
Spinocerebellar ataxias caused by polyglutamine expansions: A review of therapeutic strategies
Underwood, B. R., & Rubinsztein, D. C. (2008) · The Cerebellum · doi:10.1007/s12311-008-0026-z · Cited by 44
“Mutant huntingtin increases the susceptibility of the mitochondria to calcium-dependent permeability transition and therefore cytochrome c release ( 42 ).”
BackgroundPuranam, K. L., Wu, G., Strittmatter, W. J., & Burke, J. R. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.01.007 · Cited by 44
Cell Rearrangement and Oxidant/Antioxidant Imbalance in Huntington’s Disease
D’Egidio, F., Castelli, V., Cimini, A., & d’Angelo, M. (2023) · Antioxidants · doi:10.3390/antiox12030571 · Cited by 42
Quintanilla, R. A., Tapia‐Rojas, C., & Maria Jose Perez, J. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.09.054 · Cited by 42
Guo, X. L., & Qi, X. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.11.026 · Cited by 43
“Moreover, incubation of isolated mitochondria with recombinant mtHtt protein leads to mitochondrial swelling and release of cytochrome c [10,11], suggesting direct mitochondrial injury by mtHtt.”
Vigont, V. A., Grekhnev, D. A., Lebedeva, O. S., Gusev, K. O., Volovikov, E. A., Skopin, A. Y., Bogomazova, A. N., Belikova, L. D., Zubkova, O. A., Khomyakova, E. A., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.625231 · Cited by 44
“Neurons It has been repeatedly demonstrated that mutant huntingtin has many toxic functions altering intracellular calcium signaling (Bao et al., 1996; Luthi-Carter et al., 2002; Panov et al., 2002; Tang et al., 2003, 2005; Choo et al., 2004; Fan et al., 2007; Czeredys et al., 2013; Silva et al., 2017; Chen et al., 20…”
BackgroundMitochondrial dysfunction in cellular senescence: a bridge to neurodegenerative disease
Hruby, A. J., & Higuchi‐Sanabria, R. (2025) · npj Aging · doi:10.1038/s41514-025-00291-4 · Cited by 52
“Impaired mitochondrial calcium handling is also characteristic of HD: medium spiny neurons in YAC128 mice are prone to calcium overload and subsequentmPTPopening 342 ,potentiallyduetotheactionofmHTT,which has been demonstrated to lower the calcium threshold needed for mPTP opening 343 .”
Metabolism in HD: Still a relevant mechanism?
Duan, W., Jiang, M., & Jin, J. (2014) · Movement Disorders · doi:10.1002/mds.25992 · Cited by 41
“Mitochondria incubated with mHtt had increased sensitivity to Cainduced opening of the MPT and release of cytochrome c, consistent with a direct effect of mHtt on mitochondrial Ca handling.(18) Striatal mitochondria contain more cyclophilin D than cortical mitochondria and are more sensitive to Ca-induced MPT pore ope…”
BackgroundInfluentialSlone, S. R., Lesort, M. J., & Yacoubian, T. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021720 · Cited by 40
“, 1 mM EGTA, 250 mM sucrose). Cells were then fractionated and mitochondria were isolated as previously described with minor modifications”
MethodNecrostatin-1 mitigates mitochondrial dysfunction post-spinal cord injury
Wang, Y., Wang, J., Yang, H., Zhou, J., Feng, X., Wang, H., & Tao, Y. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2014.12.061 · Cited by 41
“…lead to mitochondrial swelling and cause the outer membrane rupture, releasing cytochrome c in the SCI group, which in turn caused the cell to go through apoptosis and necrosis by activating pro-apoptotic factors and other cytokines (Choo et al., 2004; Deniaud et al., 2008; Gogvadze et al., 2010).”
The antioxidant protein Oxr1 influences aspects of mitochondrial morphology
Wu, Y., Davies, K. E., & Oliver, P. L. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.03.029 · Cited by 42
Mitophagy in Huntington's disease
Šonský, I., Vodička, P., Kepková, K. V., & Hansíková, H. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105147 · Cited by 42
“As soon as PINK1 accumulates on the OMM, it phosphorylates both Parkin and basal ubiquitin on the OMM at their Ser65.”
BackgroundInfluentialChoo, Y. S., Mao, Z., Johnson, G. V. W., & Lesort, M. J. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.05.065 · Cited by 42
Self-citationA comprehensive perspective of Huntington’s disease and mitochondrial dysfunction
Dai, Y., Wang, H., Lian, A., Li, J., Zhao, G., Hu, S., & Li, B. (2023) · Mitochondrion · doi:10.1016/j.mito.2023.03.001 · Cited by 40
de Araújo, G. W., Beyer, C., & Arnold, S. (2008) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2008.01747.x · Cited by 39
Therapeutic Approaches for Inhibition of Protein Aggregation in Huntington’s Disease
Kim, S., & Kim, K. (2014) · Experimental Neurobiology · doi:10.5607/en.2014.23.1.36 · Cited by 40
“The mHtt also affects the outer mitochondrial membrane, and induces mitochondrial permeability transition (MPT) pore opening via reduction of Ca threshold to trigger opening, which is implicated in excitotoxicity mediated neuronal cell death [39].”
BackgroundCause or compensation?—Altered neuronal Ca2+ handling in Huntington's disease
Mackay, J. P., Nassrallah, W. B., & Raymond, L. A. (2018) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12817 · Cited by 40
SUMOylation Prevents Huntingtin Fibrillization and Localization onto Lipid Membranes
Sedighi, F., Adegbuyiro, A., & Legleiter, J. A. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00509 · Cited by 40
Ostrowski, J., Klimek-Tomczak, K., Wyrwicz, L. S., Mikuła, M., Schullery, D. S., & Bomsztyk, K. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406753200 · Cited by 39
Huntington's disease: progress and potential in the field
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CNS Redox Homeostasis and Dysfunction in Neurodegenerative Diseases
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Role of mitophagy in the neurodegenerative diseases and its pharmacological advances: A review
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Mitochondrial Bioenergy in Neurodegenerative Disease: Huntington and Parkinson
Tassone, A., Meringolo, M., Ponterio, G., Bonsi, P., Schirinzi, T., & Martella, G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087221 · Cited by 42
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Mouse Models of Polyglutamine Diseases in Therapeutic Approaches: Review and Data Table. Part II
Switonski, P. M., Szlachcic, W. J., Gabka, A., Krzyżosiak, W. J., & Figiel, M. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8316-3 · Cited by 38
“Furthermore, mutant huntingtin significantly decreases the Ca threshold necessary to initiate this cascade [183].”
BackgroundLipid Membranes Influence the Ability of Small Molecules To Inhibit Huntingtin Fibrillization
Beasley, M. A., Stonebraker, A. R., Hasan, I., Kapp, K. L., Liang, B. J., Agarwal, G., Groover, S. E., Sedighi, F., & Legleiter, J. A. (2019) · Biochemistry · doi:10.1021/acs.biochem.9b00739 · Cited by 39
Huntingtin is required for ciliogenesis and neurogenesis during early Xenopus development
Haremaki, T., Deglincerti, A., & Brivanlou, A. H. (2015) · Developmental Biology · doi:10.1016/j.ydbio.2015.07.013 · Cited by 36
“…Tartakoff, 2001; Wilkinson et al., 1999), cell membrane (Kegel et al., 2009, 2005, 2000; Sharp et al., 1995; Suopanki et al., 2006), mitochondria (Choo et al., 2004; Gutekunst et al., 1998), and to be associated with microtubules (Caviston et al., 2007; Colin et al., 2008; Elias et al., 2014;…”
BackgroundThe Role of Mitochondrial Calcium Signaling in the Pathophysiology of Cancer Cells
Sterea, A. M., & Hiani, Y. E. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-12457-1_30 · Cited by 38
The neuroprotective role of attractin in neurodegeneration
Paz, J. P., Yao, H., Lim, H. S., Lu, X., & Zhang, W. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.06.014 · Cited by 37
“Mitochondrial ysfunction has been linked to different age-related neurodeenerative diseases, including PD [47], AD [1,8,44], ALS 7,42] and HD [5,49].”
BackgroundPitts, A., Dailey, K. M., Newington, J. T., Chien, A., Arseneault, R., Cann, T., Thompson, L. M., & Cumming, R. C. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.334565 · Cited by 35
“In addition, isolated mitochondria from HD mice exhibit decreasedmembrane potential, increased propensity to depolarize at lower calcium loads, and elevated sensitivity to calcium-induced cytochrome c release compared with controls (5, 6).”
BackgroundJin, Y. N., Hwang, W. Y., Jo, C., & Johnson, G. V. W. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030406 · Cited by 34
“mHtt has been proposed to impair mitochondrial function by direct interaction”
Mitochondrial and Redox-Based Therapeutic Strategies in Huntington's Disease
Fão, L., & Rego, A. C. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.8004 · Cited by 37
“Isolated mitochondria from the liver of homozygous knockin Hdh Q150/Q150 mice also demonstrated increased predisposition to PTP induction by Ca 2 + (39).”
Lipid headgroups alter huntingtin aggregation on membranes
Beasley, M. A., Groover, S. E., Valentine, S. J., & Legleiter, J. A. (2020) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2020.183497 · Cited by 36
“In HD, one potential toxic mechanisms is that htt aggregation disrupts the membrane integrity of specific organelles [29,33,35].”
BackgroundSalman, M., Tabassum, H., & Parvez, S. (2020) · Nutritional Neuroscience · doi:10.1080/1028415x.2020.1721645 · Cited by 34
“Mitochondrial dysfunction has been suggested to be involved in HD pathology as mHtt protein inhibits mitochondrial function which then causes a direct interaction with mitochondrial outer membrane and releases apoptosis inducing factors [8].”
BackgroundMetabolism in Huntington’s disease: a major contributor to pathology
Singh, A., & Agrawal, N. (2021) · Metabolic Brain Disease · doi:10.1007/s11011-021-00844-y · Cited by 34
Therapeutic approaches to preventing cell death in Huntington disease
Kaplan, A. R., & Stockwell, B. R. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.08.004 · Cited by 32
“Additionally, the researchers showed that mutant Htt was localized in the mitochondrial outer membrane in mitochondria isolated from brains of YAC72 mice (Panov et al., 2002) and from STHdhQ111/HdhQ111 cultured striatal neurons from knock-in embryonic mice (Choo et al., 2004).”
BackgroundMangrulkar, S. V., Wankhede, N. L., Kale, M. B., Upaganlawar, A. B., Taksande, B. G., Umekar, M. J., Anwer, M. K., Dailah, H. G., Mohan, S., & Behl, T. (2023) · Neurotoxicity Research · doi:10.1007/s12640-023-00647-2 · Cited by 35
FK506 ameliorates cell death features in Huntington’s disease striatal cell models
Rosenstock, T. R., de Brito, O. M., Lombardi, V., Louros, S. R., Ribeiro, M., Almeida, S., Ferreira, I. L., Oliveira, C. R., & Rego, A. C. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2011.04.009 · Cited by 33
“In addition, an association between the N-terminal portion of mHtt and the outer mitochondrial membrane (OMM) was found in brain and liver mitochondria from several HD mice and rat models (e.g. Panov et al., 2002; Choo et al., 2004), highly suggesting that this could trigger intrinsic apoptotic cell death.”
Pérez‐Navarro, E., Canals, J. M., Ginés, S., & Alberch, J. (2006) · PubMed · doi:10.14670/hh-21.1217 · Cited by 34
Rieux, M., Alpaugh, M., Sciacca, G., Saint‐Pierre, M., Masnata, M., Denis, H. L., Lévesque, S. A., Herrmann, F., Bazenet, C. E., Garneau, A. P., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0787-4 · Cited by 32
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“Study suggested that mHtt can interact with outer membrane of the mitochondria, results in mitochondrial calcium abnormalities [73].”
BackgroundBoosting mitochondrial health to counteract neurodegeneration
Burtscher, J., Romani, M., Bernardo, G., Popa, T., Ziviani, E., Hummel, F. C., Sorrentino, V., & Millet, G. P. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102289 · Cited by 36
“mHtt exon1 induced mitochondrial permeability transition pore opening Full length mHtt and mHtt exon1 Human neuroblastoma cells and ST-Hdh, isolated mouse liver mitochondria (Choo et al., 2004)”
BackgroundNrf2 Pathway in Huntington’s Disease (HD): What Is Its Role?
Tucci, P., Lattanzi, R., Severini, C., & Saso, L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315272 · Cited by 33
“In this context, the mHTT protein, by interacting with both outer and inner mitochondrial membranes, disrupts the import of mitochondrial proteins [28] and determines cell death [29].”
BackgroundKrzysztoń-Russjan, J., Zielonka, D., Jackiewicz, J., Kuśmirek, S., Bubko, I., Klimberg, A., Marcinkowski, T., & Anuszewska, E. (2012) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-012-9479-3 · Cited by 32
“There is also evidence from HD mouse models (YAC72) and from cultured HD striatal neurons expressing endogenous mutant huntingtin (STHdhQ111) that the mHTT protein associates directly with the outer mitochondrial membrane (Choo et al. 2004).”
BackgroundPolyzos, A. A., & McMurray, C. T. (2016) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.09.003 · Cited by 31
Zhang, H., Das, S., Li, Q., Dragatsis, I., Repa, J. J., Zeitlin, S. O., Hajnóczky, G., & Борисович, Б. И. (2008) · BMC Neuroscience · doi:10.1186/1471-2202-9-38 · Cited by 31
Perry, G. M., Tallaksen‐Greene, S. J., Kumar, A., Heng, M. Y., Kneynsberg, A., van Groen, T., Detloff, P. J., Albin, R. L., & Lesort, M. J. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq247 · Cited by 33
“Biochemical analyses have identified huntingtin in compartments containing vesicle-associated proteins (17), in the nucleus (18,19) and associated with organelles such as mitochondria (20).”
BackgroundResultInfluentialPeplow, P., & Martinez, B. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.310673 · Cited by 32
“…pathways being discovered or confirmed e.g., HTT involvement in calcium handling deficits and mitochondrial dysfunction (Gines et al., 2003a; Choo et al., 2004; Milakovic and Johnson 2005; Seong et al., 2005; Oliveira et al., 2006) or effects on various signaling cascades (Gines et al.,…”
BackgroundMitochondrial functional alterations in relation to pathophysiology of Huntington’s disease
Pandey, M., Mohanakumar, K. P., & Rajamma, U. (2010) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-010-9288-5 · Cited by 30
“The mhtt has been shown to directly interact with mitochondrial membranes leading to deficits in the normal functioning of the organelle (Panov et al. 2002; Choo et al. 2004).”
BackgroundInfluentialLee, S., Chu, K., Park, J., Hong, N. H., Im, W., Kang, L., Han, Z., Jung, K., Kim, M., & Kim, M. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05044.x · Cited by 31
“In HD, mutant huntingtin binds to the outer mitochondrial membrane, reduces mitochondrial calcium uptake capacity, and eventually impairs mitochondrial complex II–III activity (Panov et al. 2002; Choo et al. 2004; Beal 2005).”
BackgroundThe Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease
Bhat, S. A., Ahamad, S., Dar, N. J., Siddique, Y. H., & Nazir, A. (2023) · Current Neuropharmacology · doi:10.2174/1570159x21666230216104621 · Cited by 29
“mHtt can impair mitochondrial function and is linked to neurodegeneration in HD [101-103].”
Background
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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