Aggregation of alpha-synuclein disrupts mitochondrial metabolism and induce mitophagy via cardiolipin externalization.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
10 11 2023
10 11 2023
Historique:
received:
03
01
2023
accepted:
27
10
2023
revised:
16
10
2023
medline:
13
11
2023
pubmed:
11
11
2023
entrez:
10
11
2023
Statut:
epublish
Résumé
Accumulation of α-synuclein aggregates in the substantia nigra pars compacta is central in the pathophysiology of Parkinson's disease, leading to the degeneration of dopaminergic neurons and the manifestation of motor symptoms. Although several PD models mimic the pathological accumulation of α-synuclein after overexpression, they do not allow for controlling and monitoring its aggregation. We recently generated a new optogenetic tool by which we can spatiotemporally control the aggregation of α-synuclein using a light-induced protein aggregation system. Using this innovative tool, we aimed to characterize the impact of α-synuclein clustering on mitochondria, whose activity is crucial to maintain neuronal survival. We observed that aggregates of α-synuclein transiently and dynamically interact with mitochondria, leading to mitochondrial depolarization, lower ATP production, mitochondrial fragmentation and degradation via cardiolipin externalization-dependent mitophagy. Aggregation of α-synuclein also leads to lower mitochondrial content in human dopaminergic neurons and in mouse midbrain. Interestingly, overexpression of α-synuclein alone did not induce mitochondrial degradation. This work is among the first to clearly discriminate between the impact of α-synuclein overexpression and aggregation on mitochondria. This study thus represents a new framework to characterize the role of mitochondria in PD.
Identifiants
pubmed: 37949858
doi: 10.1038/s41419-023-06251-8
pii: 10.1038/s41419-023-06251-8
pmc: PMC10638290
doi:
Substances chimiques
alpha-Synuclein
0
Cardiolipins
0
SNCA protein, human
0
Snca protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
729Informations de copyright
© 2023. The Author(s).
Références
Cell Death Dis. 2019 Nov 12;10(11):857
pubmed: 31719530
Neurology. 2000 May 23;54(10):1916-21
pubmed: 10822429
J Neurosci. 2008 Nov 19;28(47):12305-17
pubmed: 19020024
Nat Commun. 2018 Jun 12;9(1):2293
pubmed: 29895861
J Bioenerg Biomembr. 2004 Aug;36(4):375-9
pubmed: 15377875
Neuron. 2003 Sep 11;39(6):889-909
pubmed: 12971891
Nat Rev Neurosci. 2013 Jan;14(1):38-48
pubmed: 23254192
Science. 2003 Dec 5;302(5651):1772-5
pubmed: 14657500
Eur J Neurosci. 2010 Jul;32(2):231-40
pubmed: 20946113
J Mol Biol. 2019 Jun 28;431(14):2581-2598
pubmed: 31034892
Science. 2019 Nov 15;366(6467):818-822
pubmed: 31727826
Brain Res. 2004 Apr 9;1004(1-2):83-90
pubmed: 15033422
DNA Cell Biol. 2020 Aug;39(8):1421-1430
pubmed: 32397749
Neuron. 2008 Dec 10;60(5):748-66
pubmed: 19081372
Front Neurosci. 2018 Jun 07;12:388
pubmed: 29930495
J Cell Biol. 2010 Apr 19;189(2):211-21
pubmed: 20404107
Science. 2003 Oct 31;302(5646):841
pubmed: 14593171
Mov Disord. 2016 Feb;31(2):169-77
pubmed: 26790375
Biochim Biophys Acta. 2012 Mar;1818(3):512-9
pubmed: 22155643
J Cell Biol. 2014 Mar 31;204(7):1087-98
pubmed: 24687278
J Neurosci. 2005 Feb 23;25(8):2002-9
pubmed: 15728840
Methods Mol Biol. 2017;1567:231-243
pubmed: 28276022
Cold Spring Harb Perspect Med. 2011 Sep;1(1):a009316
pubmed: 22229125
Anal Biochem. 2004 Mar 1;326(1):13-20
pubmed: 14769330
J Neurochem. 1990 Dec;55(6):2142-5
pubmed: 2121905
Nature. 1997 Aug 28;388(6645):839-40
pubmed: 9278044
Cell Death Dis. 2019 Dec 9;10(12):940
pubmed: 31819039
J Biol Chem. 2012 May 25;287(22):17914-29
pubmed: 22453917
J Biol Chem. 2011 Jun 10;286(23):20710-26
pubmed: 21489994
J Cell Biol. 1998 Oct 19;143(2):351-8
pubmed: 9786947
Neurobiol Aging. 2011 May;32(5):857-63
pubmed: 19560232
ACS Chem Neurosci. 2019 Aug 21;10(8):3815-3829
pubmed: 31356747
Cell. 2017 Jan 12;168(1-2):159-171.e14
pubmed: 28041848
Oncogene. 2003 Nov 13;22(51):8370-8
pubmed: 14614460
J Cell Biol. 2008 Dec 1;183(5):795-803
pubmed: 19029340
Annu Rev Physiol. 2016;78:505-31
pubmed: 26667075
Curr Aging Sci. 2014;7(3):155-60
pubmed: 25612740
Biochim Biophys Acta Mol Cell Res. 2017 Jan;1864(1):169-176
pubmed: 28340937
Essays Biochem. 2018 Jul 20;62(3):341-360
pubmed: 30030364
Science. 2020 Mar 20;367(6484):1366-1371
pubmed: 32193326
Biochim Biophys Acta. 1997 Apr 3;1325(1):108-16
pubmed: 9106488
J Neurosci Res. 2021 Nov;99(11):2932-2947
pubmed: 34510532
J Biol Chem. 2010 Nov 5;285(45):34885-98
pubmed: 20805224
Cell Mol Life Sci. 2022 May 30;79(6):327
pubmed: 35637383
Nat Commun. 2014 Sep 18;5:4925
pubmed: 25233328
J Neurochem. 1990 Mar;54(3):823-7
pubmed: 2154550
PLoS Biol. 2022 Mar 9;20(3):e3001578
pubmed: 35263320
PLoS Biol. 2010 Jan 26;8(1):e1000298
pubmed: 20126261
Mol Neurobiol. 2022 Feb;59(2):1273-1284
pubmed: 34984585
J Neurosci. 2014 Jan 1;34(1):249-59
pubmed: 24381286
Nat Rev Neurol. 2013 Jan;9(1):13-24
pubmed: 23183883
Cell Res. 2014 Jul;24(7):787-95
pubmed: 24903109
Neuropathol Appl Neurobiol. 2016 Feb;42(1):77-94
pubmed: 26613567
Neurosci Lett. 2010 Mar 12;472(1):47-52
pubmed: 20117172
Neurobiol Dis. 2020 Dec;146:105086
pubmed: 32971232
Cell Death Differ. 2016 Jul;23(7):1140-51
pubmed: 26742431
J Parkinsons Dis. 2011;1(4):359-71
pubmed: 23933657
Nat Cell Biol. 2013 Oct;15(10):1197-1205
pubmed: 24036476
J Biol Chem. 2001 Jan 26;276(4):2380-6
pubmed: 11060312
Neuroscience. 2001;104(3):901-12
pubmed: 11440819
J Neurosci. 2019 Mar 6;39(10):1930-1943
pubmed: 30626699
Nat Cell Biol. 2016 May 27;18(6):579-86
pubmed: 27230526
Nat Commun. 2018 Feb 26;9(1):817
pubmed: 29483518
Acta Neuropathol. 2017 Jul;134(1):129-149
pubmed: 28337542
Sci Transl Med. 2016 Jun 8;8(342):342ra78
pubmed: 27280685
Transl Neurodegener. 2017 Oct 25;6:28
pubmed: 29090092