Alpha-synuclein prevents the formation of spherical mitochondria and apoptosis under oxidative stress

Scientific Reports

Volumn 7, Issue , 2017, Pages

  Menges, Stefanie ^a   Minakaki, Georgia ^a   Schaefer, Patrick M ^b   Meixner, Holger ^a   Prots, Iryna ^c   Schlötzer Schrehardt, Ursula ^a   Friedland, Kristina ^c   Winner, Beate ^c   Outeiro, Tiago F ^d,e   Winklhofer, Konstanze F ^f   Von Arnim, Christine A F ^b   Xiang, Wei ^c   Winkler, Jürgen ^a   Klucken, Jochen ^a  

^a UNIVERSITY HOSPITAL ERLANGEN   (Germany)

^b UNIVERSITY OF ULM   (Germany)

^c UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

^d UNIVERSITY MEDICAL CENTER GÖTTINGEN   (Germany)

^e MAX PLANCK INSTITUTE OF EXPERIMENTAL MEDICINE   (Germany)

^f RUHR UNIVERSITY BOCHUM   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA SYNUCLEIN; CARRIER PROTEIN; CASPASE 3; DNM1L PROTEIN, HUMAN; GUANOSINE TRIPHOSPHATASE; HYDROGEN PEROXIDE; MFN1 PROTEIN, HUMAN; MICROTUBULE ASSOCIATED PROTEIN; MITOCHONDRIAL PROTEIN; OPA1 PROTEIN, HUMAN; PARKIN; ROTENONE; UBIQUITIN PROTEIN LIGASE;

ANIMAL; APOPTOSIS; CELL CULTURE; CYTOLOGY; DRUG EFFECT; HUMAN; METABOLISM; MITOCHONDRIAL DYNAMICS; MITOCHONDRION; MITOPHAGY; NERVE CELL; OXIDATIVE STRESS; RAT;

ALPHA-SYNUCLEIN; ANIMALS; APOPTOSIS; CASPASE 3; CELLS, CULTURED; GTP PHOSPHOHYDROLASES; HUMANS; HYDROGEN PEROXIDE; MICROTUBULE-ASSOCIATED PROTEINS; MITOCHONDRIA; MITOCHONDRIAL DEGRADATION; MITOCHONDRIAL DYNAMICS; MITOCHONDRIAL MEMBRANE TRANSPORT PROTEINS; MITOCHONDRIAL PROTEINS; NEURONS; OXIDATIVE STRESS; RATS; ROTENONE; UBIQUITIN-PROTEIN LIGASES;

EID: 85013831514     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep42942     Document Type: Article

References (97)

1. Maroteaux, L., Campanelli, J. T. & Scheller, R. H. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. The Journal of neuroscience: the official journal of the Society for Neuroscience 8, 2804-2815 (1988).
2. Petrucci, S., Ginevrino, M. & Valente, E. M. Phenotypic spectrum of alpha-synuclein mutations: New insights from patients and cellular models. Parkinsonism & related disorders 22 Suppl 1, S16-20, doi: 10.1016/j.parkreldis.2015.08.015 (2016).
3. Spillantini, M. G. et al. Alpha-synuclein in Lewy bodies. Nature 388, 839-840, doi: 10.1038/42166 (1997).
4. Dias, V., Junn, E. & Mouradian, M. M. The role of oxidative stress in Parkinsons disease. Journal of Parkinsons disease 3, 461-491, doi: 10.3233/JPD-130230 (2013).
5. Lin, M. T. & Beal, M. F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787-795, doi: 10.1038/nature05292 (2006).
6. Marchi, S. et al. Mitochondria-ros crosstalk in the control of cell death and aging. Journal of signal transduction 2012, 329635, doi: 10.1155/2012/329635 (2012).
7. Ryan, B. J., Hoek, S., Fon, E. A. & Wade-Martins, R. Mitochondrial dysfunction and mitophagy in Parkinsons: from familial to sporadic disease. Trends in biochemical sciences 40, 200-210, doi: 10.1016/j.tibs.2015.02.003 (2015).
8. Ashrafi, G. & Schwarz, T. L. The pathways of mitophagy for quality control and clearance of mitochondria. Cell death and differentiation 20, 31-42, doi: 10.1038/cdd.2012.81 (2013).
9. Friedman, J. R. & Nunnari, J. Mitochondrial form and function. Nature 505, 335-343, doi: 10.1038/nature12985 (2014).
10. Exner, N., Lutz, A. K., Haass, C. & Winklhofer, K. F. Mitochondrial dysfunction in Parkinsons disease: molecular mechanisms and pathophysiological consequences. The EMBO journal 31, 3038-3062, doi: 10.1038/emboj.2012.170 (2012).
11. Winklhofer, K. F. Parkin and mitochondrial quality control: toward assembling the puzzle. Trends in cell biology 24, 332-341, doi: 10.1016/j.tcb.2014.01.001 (2014).
12. Pickrell, A. M. & Youle, R. J. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinsons disease. Neuron 85, 257-273, doi: 10.1016/j.neuron.2014.12.007 (2015).
13. Hashimoto, M. et al. alpha-Synuclein protects against oxidative stress via inactivation of the c-Jun N-terminal kinase stress-signaling pathway in neuronal cells. The Journal of biological chemistry 277, 11465-11472, doi: 10.1074/jbc.M111428200 (2002).
14. Musgrove, R. E., King, A. E. & Dickson, T. C. alpha-Synuclein protects neurons from apoptosis downstream of free-radical production through modulation of the MAPK signalling pathway. Neurotoxicity research 23, 358-369, doi: 10.1007/s12640-012- 9352-5 (2013).
15. Nulton-Persson, A. C. & Szweda, L. I. Modulation of mitochondrial function by hydrogen peroxide. The Journal of biological chemistry 276, 23357-23361, doi: 10.1074/jbc.M100320200 (2001).
16. Tsang, A. H. & Chung, K. K. Oxidative and nitrosative stress in Parkinsons disease. Biochimica et biophysica acta 1792, 643-650, doi: 10.1016/j.bbadis.2008.12.006 (2009).
17. Moore, D. J., West, A. B., Dawson, V. L. & Dawson, T. M. Molecular pathophysiology of Parkinsons disease. Annual review of neuroscience 28, 57-87, doi: 10.1146/annurev.neuro.28.061604.135718 (2005).
18. Hanrott, K., Gudmunsen, L., ONeill, M. J. & Wonnacott, S. 6-hydroxydopamine-induced apoptosis is mediated via extracellular auto-oxidation and caspase 3-dependent activation of protein kinase Cdelta. The Journal of biological chemistry 281, 5373-5382, doi: 10.1074/jbc.M511560200 (2006).
19. Iglesias-Gonzalez, J. et al. Differential toxicity of 6-hydroxydopamine in SH-SY5Y human neuroblastoma cells and rat brain mitochondria: protective role of catalase and superoxide dismutase. Neurochemical research 37, 2150-2160, doi: 10.1007/s11064- 012-0838-6 (2012).
20. Otera, H., Ishihara, N. & Mihara, K. New insights into the function and regulation of mitochondrial fission. Biochimica et biophysica acta 1833, 1256-1268, doi: 10.1016/j.bbamcr.2013.02.002 (2013).
21. Lackner, L. L. & Nunnari, J. M. The molecular mechanism and cellular functions of mitochondrial division. Biochimica et biophysica acta 1792, 1138-1144, doi: 10.1016/j.bbadis.2008.11.011 (2009).
22. Cassidy-Stone, A. et al. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Developmental cell 14, 193-204, doi: 10.1016/j.devcel.2007.11.019 (2008).
23. Yoon, Y., Krueger, E. W., Oswald, B. J. & McNiven, M. A. The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Molecular and cellular biology 23, 5409-5420 (2003).
24. James, D. I., Parone, P. A., Mattenberger, Y. & Martinou, J. C. hFis1, a novel component of the mammalian mitochondrial fission machinery. The Journal of biological chemistry 278, 36373-36379, doi: 10.1074/jbc.M303758200 (2003).
25. Santel, A. et al. Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells. Journal of cell science 116, 2763-2774, doi: 10.1242/jcs.00479 (2003).
26. Zorzano, A., Liesa, M., Sebastian, D., Segales, J. & Palacin, M. Mitochondrial fusion proteins: dual regulators of morphology and metabolism. Seminars in cell & developmental biology 21, 566-574, doi: 10.1016/j.semcdb.2010.01.002 (2010).
27. Song, Z., Chen, H., Fiket, M., Alexander, C. & Chan, D. C. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. The Journal of cell biology 178, 749-755, doi: 10.1083/jcb.200704110 (2007).
28. Baker, M. J. et al. Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics. The EMBO journal 33, 578-593, doi: 10.1002/embj.201386474 (2014).
29. Duvezin-Caubet, S. et al. Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology. The Journal of biological chemistry 281, 37972-37979, doi: 10.1074/jbc.M606059200 (2006).
30. Pieri, L., Madiona, K. & Melki, R. Structural and functional properties of prefibrillar alpha-synuclein oligomers. Scientific reports 6, 24526, doi: 10.1038/srep24526 (2016).
31. Lashuel, H. A. et al. Alpha-synuclein, especially the Parkinsons disease-associated mutants, forms pore-like annular and tubular protofibrils. Journal of molecular biology 322, 1089-1102 (2002).
32. Nakamura, K. et al. Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alphasynuclein. The Journal of biological chemistry 286, 20710-20726, doi: 10.1074/jbc.M110.213538 (2011).
33. Kamp, F. et al. Inhibition of mitochondrial fusion by alpha-synuclein is rescued by PINK1, Parkin and DJ-1. The EMBO journal 29, 3571-3589, doi: 10.1038/emboj.2010.223 (2010).
34. Frank, M. et al. Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. Biochimica et biophysica acta 1823, 2297-2310, doi: 10.1016/j.bbamcr.2012.08.007 (2012).
35. Mai, S., Muster, B., Bereiter-Hahn, J. & Jendrach, M. Autophagy proteins LC3B, ATG5 and ATG12 participate in quality control after mitochondrial damage and influence lifespan. Autophagy 8, 47-62, doi: 10.4161/auto.8.1.18174 (2012).
36. Soubannier, V. et al. A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Current biology: CB 22, 135-141, doi: 10.1016/j.cub.2011.11.057 (2012).
37. Tanaka, A. et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. The Journal of cell biology 191, 1367-1380, doi: 10.1083/jcb.201007013 (2010).
38. Narendra, D., Tanaka, A., Suen, D. F. & Youle, R. J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. The Journal of cell biology 183, 795-803, doi: 10.1083/jcb.200809125 (2008).
39. Geisler, S. et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nature cell biology 12, 119-131, doi: 10.1038/ncb2012 (2010).
40. Heo, J. M., Ordureau, A., Paulo, J. A., Rinehart, J. & Harper, J. W. The PINK1-PARKIN Mitochondrial Ubiquitylation Pathway Drives a Program of OPTN/NDP52 Recruitment and TBK1 Activation to Promote Mitophagy. Molecular cell 60, 7-20, doi: 10.1016/j. molcel.2015.08.016 (2015).
41. Kannan, K. & Jain, S. K. Oxidative stress and apoptosis. Pathophysiology: the official journal of the International Society for Pathophysiology/ISP 7, 153-163 (2000).
42. Sherer, T. B. et al. Mechanism of toxicity in rotenone models of Parkinsons disease. The Journal of neuroscience: the official journal of the Society for Neuroscience 23, 10756-10764 (2003).
43. Benard, G. et al. Mitochondrial bioenergetics and structural network organization. Journal of cell science 120, 838-848, doi: 10.1242/ jcs.03381 (2007).
44. Glinka, Y., Tipton, K. F. & Youdim, M. B. Nature of inhibition of mitochondrial respiratory complex I by 6-Hydroxydopamine. Journal of neurochemistry 66, 2004-2010 (1996).
45. Hyslop, P. A., Zhang, Z., Pearson, D. V. & Phebus, L. A. Measurement of striatal H2O2 by microdialysis following global forebrain ischemia and reperfusion in the rat: correlation with the cytotoxic potential of H2O2 in vitro. Brain research 671, 181-186 (1995).
46. Barsoum, M. J. et al. Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. The EMBO journal 25, 3900-3911, doi: 10.1038/sj.emboj.7601253 (2006).
47. Liot, G. et al. Complex II inhibition by 3-NP causes mitochondrial fragmentation and neuronal cell death via an NMDA- and ROSdependent pathway. Cell death and differentiation 16, 899-909, doi: 10.1038/cdd.2009.22 (2009).
48. Fan, X., Hussien, R. & Brooks, G. A. H2O2-induced mitochondrial fragmentation in C2C12 myocytes. Free radical biology and medicine 49, 1646-1654, doi: 10.1016/j.freeradbiomed.2010.08.024 (2010).
49. Iqbal, S. & Hood, D. A. Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts. American journal of physiology. Cell physiology 306, C1176-1183, doi: 10.1152/ajpcell.00017.2014 (2014).
50. Lee, H. J., Shin, S. Y., Choi, C., Lee, Y. H. & Lee, S. J. Formation and removal of alpha-synuclein aggregates in cells exposed to mitochondrial inhibitors. The Journal of biological chemistry 277, 5411-5417, doi: 10.1074/jbc.M105326200 (2002).
51. Ding, W. X. et al. Parkin and mitofusins reciprocally regulate mitophagy and mitochondrial spheroid formation. The Journal of biological chemistry 287, 42379-42388, doi: 10.1074/jbc.M112.413682 (2012).
52. Guardia-Laguarta, C. et al. alpha-Synuclein is localized to mitochondria-associated ER membranes. The Journal of neuroscience: the official journal of the Society for Neuroscience 34, 249-259, doi: 10.1523/JNEUROSCI.2507-13.2014 (2014).
53. Zhao, J. et al. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene 32, 4814-4824, doi: 10.1038/onc.2012.494 (2013).
54. Zou, J. et al. Autophagy inhibitor LRPPRC suppresses mitophagy through interaction with mitophagy initiator Parkin. PloS one 9, e94903, doi: 10.1371/journal.pone.0094903 (2014).
55. Hall, A. R. et al. Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction. Cell death & disease 7, e2238, doi: 10.1038/cddis.2016.139 (2016).
56. Rappold, P. M. et al. Drp1 inhibition attenuates neurotoxicity and dopamine release deficits in vivo. Nature communications 5, 5244, doi: 10.1038/ncomms6244 (2014).
57. Berthet, A. et al. Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons. The Journal of neuroscience: the official journal of the Society for Neuroscience 34, 14304-14317, doi: 10.1523/JNEUROSCI.0930-14.2014 (2014).
58. Santos, D., Esteves, A. R., Silva, D. F., Januario, C. & Cardoso, S. M. The Impact of Mitochondrial Fusion and Fission Modulation in Sporadic Parkinsons Disease. Molecular neurobiology 52, 573-586, doi: 10.1007/s12035-014-8893-4 (2015).
59. Stafa, K. et al. Functional interaction of Parkinsons disease-associated LRRK2 with members of the dynamin GTPase superfamily. Human molecular genetics 23, 2055-2077, doi: 10.1093/hmg/ddt600 (2014).
60. Osellame, L. D., Blacker, T. S. & Duchen, M. R. Cellular and molecular mechanisms of mitochondrial function. Best practice and research. Clinical endocrinology & metabolism 26, 711-723, doi: 10.1016/j.beem.2012.05.003 (2012).
61. Yu, T., Robotham, J. L. & Yoon, Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proceedings of the National Academy of Sciences of the United States of America 103, 2653-2658, doi: 10.1073/pnas.0511154103 (2006).
62. Korshunov, S. S., Skulachev, V. P. & Starkov, A. A. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS letters 416, 15-18 (1997).
63. Banki, K., Hutter, E., Gonchoroff, N. J. & Perl, A. Elevation of mitochondrial transmembrane potential and reactive oxygen intermediate levels are early events and occur independently from activation of caspases in Fas signaling. J Immunol 162, 1466-1479 (1999).
64. Matarrese, P., Cauda, R. & Malorni, W. Activation-associated mitochondrial hyperpolarization hijacks T cells toward an apoptosissensitized phenotype. Cell death and differentiation 10, 609-611, doi: 10.1038/sj.cdd.4401212 (2003).
65. Li, P. F., Dietz, R. & von Harsdorf, R. p53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c-independent apoptosis blocked by Bcl-2. The EMBO journal 18, 6027-6036, doi: 10.1093/emboj/18.21.6027 (1999).
66. Puskas, F., Gergely, P. Jr., Banki, K. & Perl, A. Stimulation of the pentose phosphate pathway and glutathione levels by dehydroascorbate, the oxidized form of vitamin C. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 14, 1352-1361 (2000).
67. Poppe, M. et al. Dissipation of potassium and proton gradients inhibits mitochondrial hyperpolarization and cytochrome c release during neural apoptosis. The Journal of neuroscience: the official journal of the Society for Neuroscience 21, 4551-4563 (2001).
68. Peters, S., Griebsch, M., Klemm, M., Haueisen, J. & Hammer, M. Hydrogen peroxide modulates energy metabolism and oxidative stress in cultures of permanent human Muller cells MIO-M1. Journal of biophotonics, doi: 10.1002/jbio.201600201 (2016).
69. Kholodilov, N. G. et al. Increased expression of rat synuclein in the substantia nigra pars compacta identified by mRNA differential display in a model of developmental target injury. Journal of neurochemistry 73, 2586-2599 (1999).
70. Quilty, M. C. et al. Alpha-synuclein is upregulated in neurones in response to chronic oxidative stress and is associated with neuroprotection. Experimental neurology 199, 249-256, doi: 10.1016/j.expneurol.2005.10.018 (2006).
71. Alves Da Costa, C., Paitel, E., Vincent, B. & Checler, F. Alpha-synuclein lowers p53-dependent apoptotic response of neuronal cells. Abolishment by 6-hydroxydopamine and implication for Parkinsons disease. The Journal of biological chemistry 277, 50980-50984, doi: 10.1074/jbc.M207825200 (2002).
72. Xiang, W. et al. Posttranslational modification and mutation of histidine 50 trigger alpha synuclein aggregation and toxicity. Molecular neurodegeneration 10, 8, doi: 10.1186/s13024-015-0004-0 (2015).
73. Jiang, H. et al. Parkinsons disease genetic mutations increase cell susceptibility to stress: mutant alpha-synuclein enhances H2O2- and Sin-1-induced cell death. Neurobiology of aging 28, 1709-1717, doi: 10.1016/j.neurobiolaging.2006.07.017 (2007).
74. Junn, E. & Mouradian, M. M. Human alpha-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine. Neuroscience letters 320, 146-150 (2002).
75. Lee, M., Hyun, D., Halliwell, B. & Jenner, P. Effect of the overexpression of wild-type or mutant alpha-synuclein on cell susceptibility to insult. Journal of neurochemistry 76, 998-1009 (2001).
76. Kanda, S., Bishop, J. F., Eglitis, M. A., Yang, Y. & Mouradian, M. M. Enhanced vulnerability to oxidative stress by alpha-synuclein mutations and C-terminal truncation. Neuroscience 97, 279-284 (2000).
77. Xiang, W. et al. Oxidative stress-induced posttranslational modifications of alpha-synuclein: specific modification of alphasynuclein by 4-hydroxy-2-nonenal increases dopaminergic toxicity. Molecular and cellular neurosciences 54, 71-83, doi: 10.1016/j. mcn.2013.01.004 (2013).
78. Giasson, B. I. et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290, 985-989 (2000).
79. Alves da Costa, C. et al. 6-Hydroxydopamine but not 1-methyl-4-phenylpyridinium abolishes alpha-synuclein anti-apoptotic phenotype by inhibiting its proteasomal degradation and by promoting its aggregation. The Journal of biological chemistry 281, 9824-9831, doi: 10.1074/jbc.M513903200 (2006).
80. Yuan, Y. H. et al. The molecular mechanism of rotenone-induced alpha-synuclein aggregation: emphasizing the role of the calcium/ GSK3beta pathway. Toxicology letters 233, 163-171, doi: 10.1016/j.toxlet.2014.11.029 (2015).
81. Hasegawa, T. et al. Accelerated alpha-synuclein aggregation after differentiation of SH-SY5Y neuroblastoma cells. Brain research 1013, 51-59, doi: 10.1016/j.brainres.2004.04.018 (2004).
82. Ostrerova-Golts, N. et al. The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. The Journal of neuroscience: the official journal of the Society for Neuroscience 20, 6048-6054 (2000).
83. Cole, N. B., Dieuliis, D., Leo, P., Mitchell, D. C. & Nussbaum, R. L. Mitochondrial translocation of alpha-synuclein is promoted by intracellular acidification. Experimental cell research 314, 2076-2089, doi: 10.1016/j.yexcr.2008.03.012 (2008).
84. Scholz, D. et al. Rapid, complete and large-scale generation of post-mitotic neurons from the human LUHMES cell line. Journal of neurochemistry 119, 957-971, doi: 10.1111/j.1471-4159.2011.07255.x (2011).
85. Winner, B. et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proceedings of the National Academy of Sciences of the United States of America 108, 4194-4199, doi: 10.1073/pnas.1100976108 (2011).
86. Tiscornia, G., Singer, O. & Verma, I. M. Production and purification of lentiviral vectors. Nature protocols 1, 241-245, doi: 10.1038/ nprot.2006.37 (2006).
87. Havlicek, S. et al. Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients neurons. Human molecular genetics 23, 2527-2541, doi: 10.1093/hmg/ddt644 (2014).
88. Nuber, S. et al. A progressive dopaminergic phenotype associated with neurotoxic conversion of alpha-synuclein in BAC-transgenic rats. Brain: a journal of neurology 136, 412-432, doi: 10.1093/brain/aws358 (2013).
89. Emmanouilidou, E. et al. GABA transmission via ATP-dependent K+ channels regulates alpha-synuclein secretion in mouse striatum. Brain: a journal of neurology 139, 871-890, doi: 10.1093/brain/awv403 (2016).
90. Klucken, J. et al. Alpha-synuclein aggregation involves a bafilomycin A 1-sensitive autophagy pathway. Autophagy 8, 754-766, doi: 10.4161/auto.19371 (2012).
91. Winklhofer, K. F., Henn, I. H., Kay-Jackson, P. C., Heller, U. & Tatzelt, J. Inactivation of parkin by oxidative stress and C-terminal truncations: a protective role of molecular chaperones. J Biol Chem 278, 47199-47208, doi: 10.1074/jbc.M306769200 (2003).
92. Dagda, R. K. et al. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. The Journal of biological chemistry 284, 13843-13855, doi: 10.1074/jbc.M808515200 (2009).
93. Wieckowski, M. R., Giorgi, C., Lebiedzinska, M., Duszynski, J. & Pinton, P. Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells. Nature protocols 4, 1582-1590, doi: 10.1038/nprot.2009.151 (2009).
94. Tofaris, G. K. et al. Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders. The Journal of neuroscience: the official journal of the Society for Neuroscience 26, 3942-3950, doi: 10.1523/JNEUROSCI.4965-05.2006 (2006).
95. Morciano, G. et al. Mcl-1 involvement in mitochondrial dynamics is associated with apoptotic cell death. Molecular biology of the cell 27, 20-34, doi: 10.1091/mbc.E15-01-0028 (2016).
96. Schaefer, P. M., von Einem, B., Walther, P., Calzia, E. & von Arnim, C. A. F. Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration. PLoS ONE 11, doi: 10.1371/journal. pone.0168157 (2016).
97. Bertholet, A. M. et al. Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity. Neurobiology of disease 90, 3-19, doi: 10.1016/j.nbd.2015.10.011 (2016).