Impaired mitochondrial-endoplasmic reticulum interaction and mitophagy in Miro1-mutant neurons in Parkinson's disease.
Calcium
/ metabolism
Cell Differentiation
/ genetics
Cytosol
/ metabolism
Endoplasmic Reticulum
/ genetics
Homeostasis
/ genetics
Humans
Induced Pluripotent Stem Cells
/ metabolism
Mitochondria
/ genetics
Mitochondrial Dynamics
/ genetics
Mitochondrial Proteins
/ genetics
Mitophagy
/ genetics
Neurons
/ metabolism
Parkinson Disease
/ genetics
rho GTP-Binding Proteins
/ genetics
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
28 05 2020
28 05 2020
Historique:
received:
19
12
2019
revised:
31
03
2020
accepted:
01
04
2020
pubmed:
14
4
2020
medline:
7
8
2021
entrez:
14
4
2020
Statut:
ppublish
Résumé
Mitochondrial Rho GTPase 1 (Miro1) protein is a well-known adaptor for mitochondrial transport and also regulates mitochondrial quality control and function. Furthermore, Miro1 was associated with mitochondrial-endoplasmic reticulum (ER) contact sites (MERCs), which are key regulators of cellular calcium homeostasis and the initiation of autophagy. Impairments of these mechanisms were linked to neurodegeneration in Parkinson's disease (PD). We recently revealed that PD fibroblasts harboring Miro1 mutations displayed dysregulations in MERC organization and abundance, affecting mitochondrial homeostasis and clearance. We hypothesize that mutant Miro1 impairs the function of MERCs and mitochondrial dynamics, altering neuronal homeostasis and integrity in PD. PD skin fibroblasts harboring the Miro1-R272Q mutation were differentiated into patient-derived neurons. Live-cell imaging and immunocytochemistry were used to study mitophagy and the organization and function of MERCs. Markers of autophagy or mitochondrial function were assessed by western blotting. Quantification of organelle juxtapositions revealed an increased number of MERCs in patient-derived neurons. Live-cell imaging results showed alterations of mitochondrial dynamics and increased sensitivity to calcium stress, as well as reduced mitochondrial clearance. Finally, western blot analysis indicated a blockage of the autophagy flux in Miro1-mutant neurons. Miro1-mutant neurons display altered ER-mitochondrial tethering compared with control neurons. This alteration likely interferes with proper MERC function, contributing to a defective autophagic flux and cytosolic calcium handling capacity. Moreover, mutant Miro1 affects mitochondrial dynamics in neurons, which may result in disrupted mitochondrial turnover and altered mitochondrial movement.
Identifiants
pubmed: 32280985
pii: 5816586
doi: 10.1093/hmg/ddaa066
pmc: PMC7254851
doi:
Substances chimiques
Mitochondrial Proteins
0
RHOT1 protein, human
EC 3.6.1.-
rho GTP-Binding Proteins
EC 3.6.5.2
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1353-1364Informations de copyright
© The Author(s) 2020. Published by Oxford University Press.
Références
Sci Rep. 2016 Sep 08;6:33019
pubmed: 27605430
J Neurosci. 2018 May 16;38(20):4666-4677
pubmed: 29686046
Dev Cell. 2014 Feb 24;28(4):450-8
pubmed: 24530295
J Neurosci. 2009 Jan 14;29(2):444-53
pubmed: 19144844
Biochem Biophys Res Commun. 2006 Jun 2;344(2):500-10
pubmed: 16630562
FEBS J. 2013 Dec;280(23):5981-93
pubmed: 23663200
J Cell Biol. 2010 Dec 27;191(7):1367-80
pubmed: 21173115
J Biol Chem. 2014 May 23;289(21):14569-82
pubmed: 24671417
J Biol Chem. 2008 Apr 4;283(14):9089-100
pubmed: 18245082
Methods. 2017 Feb 15;115:80-90
pubmed: 27713081
J Neurosci. 2015 Dec 2;35(48):15996-6011
pubmed: 26631479
Int J Biochem Cell Biol. 2009 Oct;41(10):1972-6
pubmed: 19481172
Curr Biol. 2017 Feb 6;27(3):371-385
pubmed: 28132811
Proc Natl Acad Sci U S A. 2018 Sep 18;115(38):E8844-E8853
pubmed: 30185553
Hum Mol Genet. 2013 Jun 1;22(11):2152-68
pubmed: 23418303
Mov Disord. 2010 Nov 15;25(15):2587-94
pubmed: 20842689
Cell Tissue Res. 2018 Jul;373(1):21-37
pubmed: 29372317
Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):E6097-E6106
pubmed: 27679849
Antioxid Redox Signal. 2019 Dec 1;31(16):1213-1234
pubmed: 31303019
Sci Rep. 2019 Jul 1;9(1):9455
pubmed: 31263238
Cell. 2011 Nov 11;147(4):893-906
pubmed: 22078885
Cold Spring Harb Perspect Biol. 2012 Nov 01;4(11):
pubmed: 23125018
J Neurosci. 2009 Apr 29;29(17):5443-55
pubmed: 19403812
Cell Rep. 2018 Apr 24;23(4):1005-1019
pubmed: 29694881
Mol Cell Neurosci. 2009 Mar;40(3):301-12
pubmed: 19103291
J Biol Chem. 2011 Jan 7;286(1):354-62
pubmed: 21036903
Acta Neuropathol. 2018 Oct;136(4):607-620
pubmed: 29923074
Nature. 2009 Oct 1;461(7264):654-8
pubmed: 19794493
Mol Cell Probes. 2016 Dec;30(6):386-396
pubmed: 27818248
Lancet Neurol. 2019 Dec;18(12):1091-1102
pubmed: 31701892
Mol Cell. 2010 Jul 9;39(1):121-32
pubmed: 20603080
J Cell Biol. 2019 Jun 3;218(6):1787-1798
pubmed: 30952800
Brain. 2017 Sep 1;140(9):2444-2459
pubmed: 29050400
J Clin Invest. 2019 Feb 1;129(2):802-819
pubmed: 30511961
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20728-33
pubmed: 19098100
J Neuropathol Exp Neurol. 1996 Mar;55(3):259-72
pubmed: 8786384
Nat Commun. 2019 Sep 27;10(1):4399
pubmed: 31562315
EMBO J. 2019 Jan 15;38(2):
pubmed: 30504269
J Cell Biol. 2008 Dec 1;183(5):795-803
pubmed: 19029340
PLoS One. 2013;8(3):e59252
pubmed: 23533608
J Cell Physiol. 2018 Sep;233(9):7080-7091
pubmed: 29574782
Biochim Biophys Acta. 2013 Apr;1832(4):495-508
pubmed: 23313576
Neuron. 2005 Aug 4;47(3):379-93
pubmed: 16055062
Int J Cell Biol. 2014;2014:709828
pubmed: 24578708
Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15456-61
pubmed: 21876166
Cell Stem Cell. 2016 Dec 1;19(6):709-724
pubmed: 27618216
Cell Rep. 2016 Oct 4;17(2):317-327
pubmed: 27705781
Nature. 2013 Mar 21;495(7441):389-93
pubmed: 23455425
Elife. 2018 Apr 20;7:
pubmed: 29676259
Neuron. 2017 Nov 1;96(3):651-666
pubmed: 29096078
Cell Metab. 2019 Dec 3;30(6):1131-1140.e7
pubmed: 31564441
J Neurosci. 2014 Jan 1;34(1):249-59
pubmed: 24381286
J Cell Mol Med. 2018 Nov;22(11):5439-5449
pubmed: 30133157
Dev Cell. 2016 Apr 18;37(2):174-189
pubmed: 27093086
Cell Stem Cell. 2010 Nov 5;7(5):618-30
pubmed: 20888316
Cell. 2009 Jan 9;136(1):163-74
pubmed: 19135897
Front Neuroanat. 2018 Dec 14;12:113
pubmed: 30618654
Pharmacol Res. 2018 Dec;138:43-56
pubmed: 30219582
Prog Neurobiol. 2019 Jun;177:73-93
pubmed: 30219247
J Neurosci. 2019 Sep 4;39(36):7074-7085
pubmed: 31300519
FEBS Lett. 2015 Dec 21;589(24 Pt A):3702-13
pubmed: 26526613
PLoS Genet. 2016 Oct 7;12(10):e1006359
pubmed: 27716788
Stem Cell Reports. 2019 May 14;12(5):878-889
pubmed: 30982740
Cell Death Dis. 2014 Apr 17;5:e1180
pubmed: 24743735
Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):14151-6
pubmed: 21825164
Neuron. 2018 Jun 27;98(6):1155-1169.e6
pubmed: 29887339
Acta Neuropathol. 2017 Jul;134(1):129-149
pubmed: 28337542