Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.
CP: Neuroscience
LHON
autophagy
cybrids
iPSCs
mitochondria
mitophagy
mtDNA
optic nerve
retinal ganglion cells
therapy
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
19 07 2022
19 07 2022
Historique:
received:
17
06
2021
revised:
27
03
2022
accepted:
29
06
2022
entrez:
20
7
2022
pubmed:
21
7
2022
medline:
23
7
2022
Statut:
ppublish
Résumé
Leber's hereditary optic neuropathy (LHON), a disease associated with a mitochondrial DNA mutation, is characterized by blindness due to degeneration of retinal ganglion cells (RGCs) and their axons, which form the optic nerve. We show that a sustained pathological autophagy and compartment-specific mitophagy activity affects LHON patient-derived cells and cybrids, as well as induced pluripotent-stem-cell-derived neurons. This is variably counterbalanced by compensatory mitobiogenesis. The aberrant quality control disrupts mitochondrial homeostasis as reflected by defective bioenergetics and excessive reactive oxygen species production, a stress phenotype that ultimately challenges cell viability by increasing the rate of apoptosis. We counteract this pathological mechanism by using autophagy regulators (clozapine and chloroquine) and redox modulators (idebenone), as well as genetically activating mitochondrial biogenesis (PGC1-α overexpression). This study substantially advances our understanding of LHON pathophysiology, providing an integrated paradigm for pathogenesis of mitochondrial diseases and druggable targets for therapy.
Identifiants
pubmed: 35858578
pii: S2211-1247(22)00930-5
doi: 10.1016/j.celrep.2022.111124
pmc: PMC9314546
pii:
doi:
Substances chimiques
DNA, Mitochondrial
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
111124Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests V.C. and C.L.M. are both involved in clinical trials with idebenone (Santhera Pharmaceuticals) in LHON patients; V.C., C.L.M., and A.A.S. are involved in gene therapy trials with Lumevoq (GenSight Biologics) in LHON patients. V.C. and A.A.S. also serve as consultants in the advisory board of Chiesi Farmaceutici.
Références
Proc Natl Acad Sci U S A. 2012 Dec 4;109(49):20065-70
pubmed: 23129651
Trans Am Ophthalmol Soc. 2000;98:223-32; discussion 232-5
pubmed: 11190025
Autophagy. 2021 Jan;17(1):1-382
pubmed: 33634751
Science. 1988 Dec 9;242(4884):1427-30
pubmed: 3201231
EMBO Rep. 2014 May;15(5):566-75
pubmed: 24671035
Nat Rev Mol Cell Biol. 2016 Apr;17(4):213-26
pubmed: 26956194
Biochim Biophys Acta Bioenerg. 2017 Aug;1858(8):615-627
pubmed: 28087257
Stem Cell Res. 2020 Oct;48:101939
pubmed: 32771908
Am J Hum Genet. 2016 Jun 2;98(6):1271
pubmed: 27259056
Biochim Biophys Acta. 2010 Feb;1797(2):197-203
pubmed: 19836344
J Biol Chem. 2010 Oct 22;285(43):33154-33164
pubmed: 20729205
Proc Natl Acad Sci U S A. 2020 Oct 13;117(41):25543-25552
pubmed: 32999071
Neurology. 2015 Oct 6;85(14):1195-201
pubmed: 26341866
Drugs. 2021 Jan;81(1):57-86
pubmed: 33159657
Biochem Biophys Res Commun. 1995 May 25;210(3):880-8
pubmed: 7763260
Methods Mol Biol. 2015;1241:181-94
pubmed: 25308497
Neurology. 2017 Jan 10;88(2):131-142
pubmed: 27974645
Arch Neurol. 2005 May;62(5):730-6
pubmed: 15883259
FEBS J. 2015 Dec;282(24):4672-8
pubmed: 26432171
Biochem Biophys Res Commun. 1997 Oct 9;239(1):139-45
pubmed: 9345284
Autophagy. 2013 Nov 1;9(11):1852-61
pubmed: 24128932
J Neurol Neurosurg Psychiatry. 2018 Apr;89(4):439-441
pubmed: 28866627
Cell Rep. 2016 Aug 30;16(9):2415-27
pubmed: 27545895
Nat Cell Biol. 2011 Feb;13(2):132-41
pubmed: 21258367
Ann Neurol. 1997 Oct;42(4):573-9
pubmed: 9382468
Brain. 2004 Oct;127(Pt 10):2183-92
pubmed: 15342361
EMBO Mol Med. 2016 Oct 4;8(10):1197-1211
pubmed: 27516453
Nat Rev Neurosci. 2005 Nov;6(11):829-40
pubmed: 16224498
Trends Cell Biol. 2018 Oct;28(10):835-867
pubmed: 30055843
Neurobiol Dis. 2007 Dec;28(3):237-50
pubmed: 17822909
Proc Natl Acad Sci U S A. 2021 Jun 15;118(24):
pubmed: 34099564
Autophagy. 2013 Sep;9(9):1367-85
pubmed: 23778835
PLoS Genet. 2018 Feb 14;14(2):e1007210
pubmed: 29444077
Brain. 2011 Jan;134(Pt 1):220-34
pubmed: 20943885
Ann Neurol. 1998 Aug;44(2):187-93
pubmed: 9708540
Trends Cell Biol. 2018 Apr;28(4):258-273
pubmed: 29409699
Sci Rep. 2019 Apr 30;9(1):6720
pubmed: 31040363
Hum Mol Genet. 2019 Feb 1;28(3):422-433
pubmed: 30304398
Eur J Med Genet. 2012 May;55(5):342-8
pubmed: 22342432
Prog Retin Eye Res. 2011 Mar;30(2):81-114
pubmed: 21112411
Curr Protoc Cell Biol. 2007 Sep;Chapter 21:Unit 21.5
pubmed: 18228502
Biomedicines. 2021 Feb 04;9(2):
pubmed: 33557057
Science. 2011 Jan 28;331(6016):456-61
pubmed: 21205641
Nat Rev Mol Cell Biol. 2018 Nov;19(11):713-730
pubmed: 30143745
Trends Genet. 2003 May;19(5):257-62
pubmed: 12711217
Biophys J. 2015 Nov 17;109(10):2067-78
pubmed: 26588566
Methods Mol Biol. 2014;1163:165-73
pubmed: 24841305
Cardiovasc Res. 2021 Aug 10;:
pubmed: 34375401
Invest Ophthalmol Vis Sci. 2009 Apr;50(4):1666-74
pubmed: 19098324
J Cell Biol. 2008 Dec 1;183(5):795-803
pubmed: 19029340
Cell. 2010 Feb 5;140(3):313-26
pubmed: 20144757
Science. 2016 Jan 15;351(6270):275-281
pubmed: 26816379
Cell Death Differ. 2016 Feb;23(2):231-41
pubmed: 26206091
Cell Metab. 2014 Apr 1;19(4):630-41
pubmed: 24703695
Invest Ophthalmol Vis Sci. 2012 Nov 09;53(12):7608-17
pubmed: 23060142
Hum Mol Genet. 2016 Feb 1;25(3):584-96
pubmed: 26647310
Cell Rep. 2017 Oct 3;21(1):1-9
pubmed: 28978464
Cell Death Dis. 2015 Dec 17;6:e2021
pubmed: 26673666
Int J Biochem Cell Biol. 2015 Jun;63:21-4
pubmed: 25666555
Nat Rev Mol Cell Biol. 2018 Nov;19(11):731-745
pubmed: 30305710
J Clin Invest. 2020 Sep 1;130(9):4935-4946
pubmed: 32516135
Mitochondrion. 2017 Sep;36:36-42
pubmed: 28093355
Mol Cell Biol. 1992 Feb;12(2):480-90
pubmed: 1732728
J Cell Sci. 2018 Sep 20;131(18):
pubmed: 30237248
PLoS Biol. 2010 Jan 26;8(1):e1000298
pubmed: 20126261
Ann Neurol. 2015 Jul;78(1):21-38
pubmed: 25820230
Science. 1989 Oct 27;246(4929):500-3
pubmed: 2814477
Nat Commun. 2020 Aug 12;11(1):4029
pubmed: 32788597
AIDS. 2005 Oct 14;19(15):1627-33
pubmed: 16184032
Brain. 2016 Mar;139(Pt 3):e17
pubmed: 26657166
Biochim Biophys Acta. 2016 Jul;1857(7):872-83
pubmed: 26721206
FEBS J. 2005 Mar;272(5):1124-35
pubmed: 15720387
Methods Mol Biol. 2021;2310:113-159
pubmed: 34096002
Neuroscience. 2012 May 3;209:64-73
pubmed: 22390943
N Engl J Med. 2013 Feb 14;368(7):651-62
pubmed: 23406030
Redox Biol. 2021 Jan;38:101812
pubmed: 33254077
J Cell Biol. 2014 Jul 21;206(2):173-82
pubmed: 25049270
Prog Retin Eye Res. 2004 Jan;23(1):53-89
pubmed: 14766317
Aging (Albany NY). 2017 Apr;9(4):1341-1350
pubmed: 28455970
Neurology. 2016 May 17;86(20):1921-3
pubmed: 27164671
Apoptosis. 2005 Oct;10(5):997-1007
pubmed: 16151635
Methods Mol Biol. 2015;1212:87-102
pubmed: 25063499
Methods Mol Biol. 2012;810:183-205
pubmed: 22057568
Brain. 2014 Feb;137(Pt 2):335-53
pubmed: 24369379
Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):378-83
pubmed: 19966284
Cell Death Differ. 2005 Nov;12 Suppl 2:1528-34
pubmed: 16247500
J Biol Chem. 2003 Feb 7;278(6):4145-50
pubmed: 12446713
Cell Signal. 2013 Jan;25(1):50-65
pubmed: 23000343
Neurology. 1997 Jun;48(6):1623-32
pubmed: 9191778
Biochim Biophys Acta. 2011 Jul;1813(7):1269-78
pubmed: 20933024
Antioxid Redox Signal. 2011 May 15;14(10):1939-51
pubmed: 21128700
Biochim Biophys Acta. 2014 Aug;1837(8):1247-56
pubmed: 24769419