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Cretin 2021 EMBO Mol Med

From Bioblast
Publications in the MiPMap
Cretin E, Lopes P, Vimont E, Tatsuta T, Langer T, Gazi A, Sachse M, Yu-Wai-Man P, Reynier P, Wai T (2021) High-throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts. EMBO Mol Med 13:13579.

Β» PMID: 34014035 Open Access]

Cretin Emma, Lopes Priscilla, Vimont Elodie, Tatsuta Takashi, Langer Thomas, Gazi Anastasia, Sachse Martin, Yu-Wai-Man Patrick, Reynier Pascal, Wai Timothy (2021) EMBO Mol Med

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. β€’ Keywords: OPA1, Genetic modifiers, High-throughput screening, Mitochondrial dynamics, Phospholipid metabolism β€’ Bioblast editor: Reiswig R β€’ O2k-Network Lab: FR Paris Wai T

Labels: MiParea: Respiration, mtDNA;mt-genetics  Pathology: Other  Stress:Mitochondrial disease  Organism: Mouse  Tissue;cell: Fibroblast  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k