Interaction of misfolded proteins and mitochondria in neurodegenerative disorders

Biochemical Society Transactions

Volumn 45, Issue 4, 2017, Pages 1025-1033

  Abramov, Andrey Y ^a   Berezhnov, Alexey V ^b   Fedotova, Evgeniya I ^b   Zinchenko, Valery P ^b   Dolgacheva, Ludmila P ^b  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b RUSSIAN ACADEMY OF SCIENCES   (Russian Federation)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 85027510422     PISSN: 03005127     EISSN: 14708752     Source Type: Journal    
DOI: 10.1042/BST20170024     Document Type: Review

References (87)

1. Selkoe, D.J. and Hardy, J. (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 8, 595–608 doi:10.15252/emmm. 201606210
2. Liu, F. and Gong, C.-X. (2008) Tau exon 10 alternative splicing and tauopathies. Mol. Neurodegener. 3, 8 doi:10.1186/1750-1326-3-8
3. Spillantini, M.G. and Goedert, M. (2013) Tau pathology and neurodegeneration. Lancet Neurol. 12, 609–622 doi:10.1016/S1474-4422(13)70090-5
4. Gandhi, S. and Wood, N.W. (2005) Molecular pathogenesis of Parkinson’s disease. Hum. Mol. Genet. 4, 2749–2755 doi:10.1093/hmg/ddi308
5. Saudou, F. and Humbert, S. (2016) The biology of huntingtin. Neuron 89, 910–926 doi:10.1016/j.neuron.2016.02.003
6. Burchell, V.S., Gandhi, S., Deas, E., Wood, N.W., Abramov, A.Y. and Plun-Favreau, H. (2010) Targeting mitochondrial dysfunction in neurodegenerative disease: part I. Expert Opin. Ther. Targets 14, 369–385 doi:10.1517/14728221003652489
7. Angelova, P.R. and Abramov, A.Y. (2016) Functional role of mitochondrial reactive oxygen species in physiology. Free Radic. Biol. Med. 100, 81–85 doi:10.1016/j.freeradbiomed.2016.06.005
8. Balaban, R.S., Nemoto, S. and Finkel, T. (2005) Mitochondria, oxidants, and aging. Cell 120, 483–495 doi:10.1016/j.cell.2005.02.001
9. Finberg, J.P.M. (2014) Update on the pharmacology of selective inhibitors of MAO-A and MAO-B: focus on modulation of CNS monoamine neurotransmitter release. Pharmacol. Ther. 143, 133–152 doi:10.1016/j.pharmthera.2014.02.010
10. Vaarmann, A., Gandhi, S. and Abramov, A.Y. (2010) Dopamine induces Ca2+ signaling in astrocytes through reactive oxygen species generated by monoamine oxidase. J. Biol. Chem. 285, 25018–25023 doi:10.1074/jbc.M110.111450
11. Ruan, L., Zhou, C., Jin, E., Kucharavy, A., Zhang, Y., Wen, Z. et al. (2017) Cytosolic proteostasis through importing of misfolded proteins into mitochondria. Nature 543, 443–446 doi:10.1038/nature21695
12. Blass, J.P. and Gibson, G.E. (1991) The role of oxidative abnormalities in the pathophysiology of Alzheimer’s disease. Rev. Neurol. 147, 513–525 PMID:1962057
13. Casley, C.S., Canevari, L., Land, J.M., Clark, J.B. and Sharpe, M.A. (2002) β-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J. Neurochem. 80, 91–100 doi:10.1046/j.0022-3042.2001.00681.x
14. Longo, V.D., Viola, K.L., Klein, W.L. and Finch, C.E. (2000) Reversible inactivation of superoxide-sensitive aconitase in Aβ1-42-treated neuronal cell lines. J. Neurochem. 75, 1977–1985 doi:10.1046/j.1471-4159.2000.0751977.x
15. Canevari, L., Clark, J.B. and Bates, T.E. (1999) β-Amyloid fragment 25-35 selectively decreases complex IV activity in isolated mitochondria. FEBS Lett. 457, 131–134 doi:10.1016/S0014-5793(99)01028-5
16. Casley, C.S., Land, J.M., Sharpe, M.A., Clark, J.B., Duchen, M.R. and Canevari, L. (2002) β-amyloid fragment 25–35 causes mitochondrial dysfunction in primary cortical neurons. Neurobiol. Dis. 10, 258–267 doi:10.1006/nbdi.2002.0516
17. Abramov, A.Y., Canevari, L. and Duchen, M.R. (2004) β-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J. Neurosci. 24, 565–575 doi:10.1523/JNEUROSCI.4042-03.2004
18. Ionov, M., Burchell, V., Klajnert, B., Bryszewska, M. and Abramov, A.Y. (2011) Mechanism of neuroprotection of melatonin against beta-amyloid neurotoxicity. Neuroscience 180, 229–237 doi:10.1016/j.neuroscience.2011.02.045
19. Abramov, A.Y., Canevari, L. and Duchen, M.R. (2003) Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity. J. Neurosci. 23, 5088–5095 PMID:12832532
20. Abramov, A.Y., Canevari, L. and Duchen, M.R. (2004) Calcium signals induced by amyloid β peptide and their consequences in neurons and astrocytes in culture. Biochim. Biophys. Acta, Mol. Cell Res. 1742, 81–87 doi:10.1016/j.bbamcr.2004.09.006
21. Abramov, A.Y. and Duchen, M.R. (2005) The role of an astrocytic NADPH oxidase in the neurotoxicity of amyloid beta peptides. Philos. Trans. R. Soc. Lond. B Biol. Sci. 360, 2309–2314 doi:10.1098/rstb.2005.1766
22. Parks, J.K., Smith, T.S., Trimmer, P.A., Bennett, Jr, J.P. and Parker, Jr, W.D. (2001) Neurotoxic Aβ peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro. J. Neurochem. 76, 1050–1056 doi:10.1046/j.1471-4159.2001.00112.x
23. Shevtzova, E.F., Kireeva, E.G. and Bachurin, S.O. (2001) Effect of β-amyloid peptide fragment 25-35 on nonselective permeability of mitochondria. Bull. Exp. Biol. Med. 132, 1173–1176 doi:10.1023/A:1014559331402
24. Abramov, A.Y., Jacobson, J., Wientjes, F., Hothersall, J., Canevari, L. and Duchen, M.R. (2005) Expression and modulation of an NADPH oxidase in mammalian astrocytes. J. Neurosci. 25, 9176–9184 doi:10.1523/JNEUROSCI.1632-05.2005
25. Abramov, A.Y., Scorziello, A. and Duchen, M.R. (2007) Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J. Neurosci. 27, 1129–1138 doi:10.1523/JNEUROSCI.4468-06.2007
26. Du, H., Guo, L., Fang, F., Chen, D., Sosunov, A.A., McKhann, G.M. et al. (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat. Med. 14, 1097–1105 doi:10.1038/nm.1868
27. Du, H., Guo, L., Yan, S., Sosunov, A.A., McKhann, G.M. and Yan, S.S. (2010) Early deficits in synaptic mitochondria in an Alzheimer’s disease mouse model. Proc. Natl Acad. Sci. U.S.A. 107, 18670–18675 doi:10.1073/pnas.1006586107
28. Caspersen, C., Wang, N., Yao, J., Sosunov, A., Chen, X., Lustbader, J.W. et al. (2005) Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease. FASEB J. 19, 2040–2041 doi:10.1096/fj.05-3735fje
29. Abeti, R., Abramov, A.Y. and Duchen, M.R. (2011) β-amyloid activates PARP causing astrocytic metabolic failure and neuronal death. Brain 134, 1658–1672 doi:10.1093/brain/awr104
30. Angelova, P.R. and Abramov, A.Y. (2014) Interaction of neurons and astrocytes underlies the mechanism of Aβ-induced neurotoxicity. Biochem. Soc. Trans. 42, 1286–1290 doi:10.1042/BST20140153
31. Wang, X., Su, B., Siedlak, S.L., Moreira, P.I., Fujioka, H., Wang, Y. et al. (2008) Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc. Natl Acad. Sci. U.S.A. 105, 19318–19323 doi:10.1073/pnas.0804871105
32. Holmström, K.M., Marina, N., Baev, A.Y., Wood, N.W., Gourine, A.V. and Abramov, A.Y. (2013) Signalling properties of inorganic polyphosphate in the mammalian brain. Nat. Commun. 4, 1362 doi:10.1038/ncomms2364
33. Angelova, P.R., Baev, A.Y., Berezhnov, A.V. and Abramov, A.Y. (2016) Role of inorganic polyphosphate in mammalian cells: from signal transduction and mitochondrial metabolism to cell death. Biochem. Soc. Trans. 44, 40–45 doi:10.1042/BST20150223
34. Pavlov, E., Aschar-Sobbi, R., Campanella, M., Turner, R.J., Gómez-García, M.R. and Abramov, A.Y. (2010) Inorganic polyphosphate and energy metabolism in mammalian cells. J. Biol. Chem. 285, 9420–9428 doi:10.1074/jbc.M109.013011
35. Cremers, C.M., Knoefler, D., Gates, S., Martin, N., Dahl, J.-U., Lempart, J. et al. (2016) Polyphosphate: a conserved modifier of amyloidogenic processes. Mol. Cell 63, 768–780 doi:10.1016/j.molcel.2016.07.016
36. Neve, R.L., Harris, P., Kosik, K.S., Kurnit, D.M. and Donlon, T.A. (1986) Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2. Mol. Brain Res. 387, 271–280 doi:10.1016/0169-328X(86) 90033-1
37. Gorath, M., Stahnke, T., Mronga, T., Goldbaum, O. and Richter-Landsberg, C. (2001) Developmental changes of tau protein and mRNA in cultured rat brain oligodendrocytes. Glia 36, 89–101 doi:10.1002/glia.1098
38. Kumar, P., Jha, N.K., Jha, S.K., Ramani, K. and Ambasta, R.K. (2015) Tau phosphorylation, molecular chaperones, and ubiquitin E3 ligase: clinical relevance in Alzheimer’s disease. J. Alzheimers. Dis. 43, 341–361 doi:10.3233/JAD-140933
39. Drubin, D.G. and Kirschner, M.W. (1986) Tau protein function in living cells. J. Cell Biol. 103, 2739–2746 doi:10.1083/jcb.103.6.2739
40. Wang, Y. and Mandelkow, E. (2016) Tau in physiology and pathology. Nat. Rev. Neurosci. 17, 5–21 doi:10.1038/nrn.2015.1
41. Mazzaro, N., Barini, E., Spillantini, M.G., Goedert, M., Medini, P. and Gasparini, L. (2016) Tau-driven neuronal and neurotrophic dysfunction in a mouse model of early tauopathy. J. Neurosci. 36, 2086–2100 doi:10.1523/JNEUROSCI.0774-15.2016
42. Spillantini, M.G. and Goedert, M. (1998) Tau protein pathology in neurodegenerative diseases. Trends Neurosci. 21, 428–433 doi:10.1016/ S0166-2236(98)01337-X
43. Stokin, G.B., Lillo, C., Falzone, T.L., Brusch, R.G., Rockenstein, E., Mount, S.L. et al. (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307, 1282–1288 doi:10.1126/science.1105681
44. Praprotnik, D., Smith, M.A., Richey, P.L., Vinters, H.V. and Perry, G. (1996) Filament heterogeneity within the dystrophic neurites of senile plaques suggests blockage of fast axonal transport in Alzheimer’s disease. Acta Neuropathol. 91, 226–235 doi:10.1007/s004010050420
45. Wang, X., Su, B., Lee, H.-G., Li, X., Perry, G., Smith, M.A. et al. (2009) Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J. Neurosci. 29, 9090–9103 doi:10.1523/JNEUROSCI.1357-09.2009
46. DuBoff, B., Götz, J. and Feany, M.B. (2012) Tau promotes neurodegeneration via DRP1 mislocalization in vivo. Neuron 75, 618–632 doi:10.1016/j. neuron.2012.06.026
47. Rhein, V., Song, X., Wiesner, A., Ittner, L.M., Baysang, G., Meier, F. et al. (2009) Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc. Natl Acad. Sci. U.S.A. 106, 20057–20062 doi:10.1073/pnas.0905529106
48. Esteras, N., Rohrer, J.D., Hardy, J., Wray, S. and Abramov, A.Y. (2017) Mitochondrial hyperpolarization in iPSC-derived neurons from patients of FTDP-17 with 10+16 MAPT mutation leads to oxidative stress and neurodegeneration. Redox Biol. 12, 410–422 doi:10.1016/j.redox.2017.03.008
49. Singleton, A.B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J. et al. (2003) β-Synuclein locus triplication causes Parkinson’s disease. Science 302, 841 doi:10.1126/science.1090278
50. Burre, J., Sharma, M., Tsetsenis, T., Buchman, V., Etherton, M.R. and Sudhof, T.C. (2010) β-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329, 1663–1667 doi:10.1126/science.1195227
51. Vargas, K.J., Makani, S., Davis, T., Westphal, C.H., Castillo, P.E. and Chandra, S.S. (2014) Synucleins regulate the kinetics of synaptic vesicle endocytosis. J. Neurosci. 34, 9364–9376 doi:10.1523/JNEUROSCI.4787-13.2014
52. Ludtmann, M.H.R., Angelova, P.R., Ninkina, N.N., Gandhi, S., Buchman, V.L. and Abramov, A.Y. (2016) Monomeric alpha-synuclein exerts a physiological role on brain ATP synthase. J. Neurosci. 36, 10510–10521 doi:10.1523/JNEUROSCI.1659-16.2016
53. Nakamura, K., Nemani, V.M., Wallender, E.K., Kaehlcke, K., Ott, M. and Edwards, R.H. (2008) Optical reporters for the conformation of α-synuclein reveal a specific interaction with mitochondria. J. Neurosci. 28, 12305–12317 doi:10.1523/JNEUROSCI.3088-08.2008
54. Cremades, N., Cohen, S.I.A., Deas, E., Abramov, A.Y., Chen, A.Y., Orte, A. et al. (2012) Direct observation of the interconversion of normal and toxic forms of α-synuclein. Cell 149, 1048–1059 doi:10.1016/j.cell.2012.03.037
55. Davidson, W.S., Jonas, A., Clayton, D.F. and George, J.M. (1998) Stabilization of α-synuclein secondary structure upon binding to synthetic membranes. J. Biol. Chem. 273, 9443–9449 doi:10.1074/jbc.273.16.9443
56. Pfefferkorn, C.M., Jiang, Z. and Lee, J.C. (2012) Biophysics of α-synuclein membrane interactions. Biochim. Biophys. Acta, Biomembr. 1818, 162–171 doi:10.1016/j.bbamem.2011.07.032
57. Rostovtseva, T.K., Gurnev, P.A., Protchenko, O., Hoogerheide, D.P., Yap, T.L., Philpott, C.C. et al. (2015) α-Synuclein shows high affinity interaction with voltage-dependent anion channel, suggesting mechanisms of mitochondrial regulation and toxicity in Parkinson disease. J. Biol. Chem. 290, 18467–18477 doi:10.1074/jbc.M115.641746
58. Shvadchak, V.V., Yushchenko, D.A., Pievo, R. and Jovin, T.M. (2011) The mode of α-synuclein binding to membranes depends on lipid composition and lipid to protein ratio. FEBS Lett. 585, 3513–3519 doi:10.1016/j.febslet.2011.10.006
59. Martin, L.J., Pan, Y., Price, A.C., Sterling, W., Copeland, N.G., Jenkins, N.A. et al. (2006) Parkinson’s disease α-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J. Neurosci. 26, 41–50 doi:10.1523/JNEUROSCI.4308-05.2006
60. Loeb, V., Yakunin, E., Saada, A. and Sharon, R. (2010) The transgenic overexpression of α-synuclein and not its related pathology associates with complex I inhibition. J. Biol. Chem. 285, 7334–7343 doi:10.1074/jbc.M109.061051
61. Luth, E.S., Stavrovskaya, I.G., Bartels, T., Kristal, B.S. and Selkoe, D.J. (2014) Soluble, prefibrillar α-synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction. J. Biol. Chem. 289, 21490–21507 doi:10.1074/jbc.M113.545749
62. Devi, L., Raghavendran, V., Prabhu, B.M., Avadhani, N.G. and Anandatheerthavarada, H.K. (2008) Mitochondrial import and accumulation of α-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J. Biol. Chem. 283, 9089–9100 doi:10.1074/jbc. M710012200
63. Reeve, A.K., Ludtmann, M.H.R., Angelova, P.R., Simcox, E.M., Horrocks, M.H., Klenerman, D. et al. (2015) Aggregated α-synuclein and complex I deficiency: exploration of their relationship in differentiated neurons. Cell Death Dis. 6, e1820 doi:10.1038/cddis.2015.166
64. Zhu, Y., Duan, C., Lü, L., Gao, H., Zhao, C., Yu, S. et al. (2011) α-Synuclein overexpression impairs mitochondrial function by associating with adenylate translocator. Int. J. Biochem. Cell Biol. 43, 732–741 doi:10.1016/j.biocel.2011.01.014
65. Nakamura, K., Nemani, V.M., Azarbal, F., Skibinski, G., Levy, J.M., Egami, K. et al. (2011) Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein α-synuclein. J. Biol. Chem. 286, 20710–20726 doi:10.1074/jbc.M110.213538
66. Mullin, S. and Schapira, A. (2013) α-Synuclein and mitochondrial dysfunction in Parkinson’s disease. Mol. Neurobiol. 47, 587–597 doi:10.1007/ s12035-013-8394-x
67. Abeti, R. and Abramov, A.Y. (2015) Mitochondrial Ca2+ in neurodegenerative disorders. Pharmacol. Res. 99, 377–381 doi:10.1016/j.phrs.2015.05.007
68. Angelova, P.R., Ludtmann, M.H.R., Horrocks, M.H., Negoda, A., Cremades, N., Klenerman, D. et al. (2016) Ca2+ is a key factor in α-synuclein-induced neurotoxicity. J. Cell Sci. 129, 1792–1801 doi:10.1242/jcs.180737
69. Zakharov, S.D., Hulleman, J.D., Dutseva, E.A., Antonenko, Y.N., Rochet, J.-C. and Cramer, W.A. (2007) Helical α-synuclein forms highly conductive ion channels. Biochemistry 46, 14369–14379 doi:10.1021/bi701275p
70. Bernardi, P., Rasola, A., Forte, M. and Lippe, G. (2015) The mitochondrial permeability transition pore: channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology. Physiol. Rev. 95, 1111–1155 doi:10.1152/physrev.00001.2015
71. Deas, E., Cremades, N., Angelova, P.R., Ludtmann, M.H.R., Yao, Z., Chen, S. et al. (2016) α-Synuclein oligomers interact with metal ions to induce oxidative stress and neuronal death in Parkinson’s disease. Antioxid. Redox Signal. 24, 376–391 doi:10.1089/ars.2015.6343
72. Angelova, P.R., Horrocks, M.H., Klenerman, D., Gandhi, S., Abramov, A.Y. and Shchepinov, M.S. (2015) Lipid peroxidation is essential for α-synuclein-induced cell death. J. Neurochem. 133, 582–589 doi:10.1111/jnc.13024
73. Hayashi, T., Rizzuto, R., Hajnoczky, G. and Su, T.-P. (2009) MAM: more than just a housekeeper. Trends Cell Biol. 19, 81–88 doi:10.1016/j.tcb.2008. 12.002
74. Hayashi, T. and Fujimoto, M. (2010) Detergent-resistant microdomains determine the localization of σ-1 receptors to the endoplasmic reticulum-mitochondria junction. Mol. Pharmacol. 77, 517–528 doi:10.1124/mol.109.062539
75. Calì, T., Ottolini, D., Negro, A. and Brini, M. (2012) α-Synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum-mitochondria interactions. J. Biol. Chem. 287, 17914–17929 doi:10.1074/jbc.M111.302794
76. Area-Gomez, E. (2014) Assessing the function of mitochondria-associated ER membranes. Methods Enzymol. 547, 181–197 doi:10.1016/ B978-0-12-801415-8.00011-4
77. Di Maio, R., Barrett, P.J., Hoffman, E.K., Barrett, C.W., Zharikov, A., Borah, A. et al. (2016) α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci. Transl. Med. 8, 342ra78 doi:10.1126/scitranslmed.aaf3634
78. Hoogeveen, A.T., Willemsen, R., Meyer, N., de Rooij, K.E., Roos, R.A.C., van Ommen, G.-J.B. et al. (1993) Characterization and localization of the Huntington disease gene product. Hum. Mol. Genet. 2, 2069–2073 doi:10.1093/hmg/2.12.2069
79. Rockabrand, E., Slepko, N., Pantalone, A., Nukala, V.N., Kazantsev, A., Marsh, J.L. et al. (2007) The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis. Hum. Mol. Genet. 16, 61–77 doi:10.1093/hmg/ddl440
80. Brandstaetter, H., Kruppa, A.J. and Buss, F. (2014) Huntingtin is required for ER-to-Golgi transport and for secretory vesicle fusion at the plasma membrane. Dis. Models Mech. 7, 1335–1340 doi:10.1242/dmm.017368
81. Rigamonti, D., Bauer, J.H., De-Fraja, C., Conti, L., Sipione, S., Sciorati, C. et al. (2000) Wild-type huntingtin protects from apoptosis upstream of caspase-3. J. Neurosci. 20, 3705–3713 PMID:10804212
82. Nasir, J., Floresco, S.B., O’Kusky, J.R., Diewert, V.M., Richman, J.M., Zeisler, J. et al. (1995) Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81, 811–823 doi:10.1016/0092-8674(95)90542-1
83. Bae, B.-I., Xu, H., Igarashi, S., Fujimuro, M., Agrawal, N., Taya, Y. et al. (2005) p53 mediates cellular dysfunction and behavioral abnormalities in Huntington’s disease. Neuron 47, 29–41 doi:10.1016/j.neuron.2005.06.005
84. Benchoua, A., Trioulier, Y., Zala, D., Gaillard, M.-C., Lefort, N., Dufour, N. et al. (2006) Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin. Mol. Biol. Cell 17, 1652–1663 doi:10.1091/mbc.E05-07-0607
85. Benchoua, A., Trioulier, Y., Diguet, E., Malgorn, C., Gaillard, M.-C., Dufour, N. et al. (2008) Dopamine determines the vulnerability of striatal neurons to the N-terminal fragment of mutant huntingtin through the regulation of mitochondrial complex, II. Hum. Mol. Genet. 17, 1446–1456 doi:10.1093/hmg/ ddn033
86. Panov, A.V., Gutekunst, C.-A., Leavitt, B.R., Hayden, M.R., Burke, J.R., Strittmatter, W.J. et al. (2002) Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat. Neurosci. 5, 731–736 doi:10.1038/nn884
87. Lim, D., Fedrizzi, L., Tartari, M., Zuccato, C., Cattaneo, E., Brini, M. et al. (2008) Calcium homeostasis and mitochondrial dysfunction in striatal neurons of Huntington disease. J. Biol. Chem. 283, 5780–5789 doi:10.1074/jbc.M704704200