Cretin, Emma, Lopes, Priscilla, Vimont, Elodie, Tatsuta, Takashi, Langer, Thomas, Gazi, Anastasia ORCID: 0000-0002-2922-3625, Sachse, Martin, Yu-Wai-Man, Patrick, Reynier, Pascal ORCID: 0000-0003-0802-4608 and Wai, Timothy ORCID: 0000-0002-6770-6222 (2021). High-throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts. EMBO Mol. Med., 13 (6). HOBOKEN: WILEY. ISSN 1757-4684

Full text not available from this repository.

Abstract

Mutations in OPA1 cause autosomal dominant optic atrophy (DOA) as well as DOA+, a phenotype characterized by more severe neurological deficits. OPA1 deficiency causes mitochondrial fragmentation and also disrupts cristae, respiration, mitochondrial DNA (mtDNA) maintenance, and cell viability. It has not yet been established whether phenotypic severity can be modulated by genetic modifiers of OPA1. We screened the entire known mitochondrial proteome (1,531 genes) to identify genes that control mitochondrial morphology using a first-in-kind imaging pipeline. We identified 145 known and novel candidate genes whose depletion promoted elongation or fragmentation of the mitochondrial network in control fibroblasts and 91 in DOA+ patient fibroblasts that prevented mitochondrial fragmentation, including phosphatidyl glycerophosphate synthase (PGS1). PGS1 depletion reduces CL content in mitochondria and rebalances mitochondrial dynamics in OPA1-deficient fibroblasts by inhibiting mitochondrial fission, which improves defective respiration, but does not rescue mtDNA depletion, cristae dysmorphology, or apoptotic sensitivity. Our data reveal that the multifaceted roles of OPA1 in mitochondria can be functionally uncoupled by modulating mitochondrial lipid metabolism, providing novel insights into the cellular relevance of mitochondrial fragmentation.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Cretin, EmmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopes, PriscillaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vimont, ElodieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tatsuta, TakashiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langer, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gazi, AnastasiaUNSPECIFIEDorcid.org/0000-0002-2922-3625UNSPECIFIED
Sachse, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yu-Wai-Man, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reynier, PascalUNSPECIFIEDorcid.org/0000-0003-0802-4608UNSPECIFIED
Wai, TimothyUNSPECIFIEDorcid.org/0000-0002-6770-6222UNSPECIFIED
URN: urn:nbn:de:hbz:38-602117
DOI: 10.15252/emmm.202013579
Journal or Publication Title: EMBO Mol. Med.
Volume: 13
Number: 6
Date: 2021
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1757-4684
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DOMINANT OPTIC ATROPHY; MARIE-TOOTH-DISEASE; PHOSPHATIDIC-ACID; INTRAMITOCHONDRIAL TRANSPORT; ABSOLUTE QUANTIFICATION; QUANTITATIVE-ANALYSIS; PROTEOLYTIC CLEAVAGE; LIPID HOMEOSTASIS; NUAGE FORMATION; FUSIONMultiple languages
Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60211

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item