High‐throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts
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 viabilit...
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202013579 |
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| author | Emma Cretin Priscilla Lopes Elodie Vimont Takashi Tatsuta Thomas Langer Anastasia Gazi Martin Sachse Patrick Yu‐Wai‐Man Pascal Reynier Timothy Wai |
| author_facet | Emma Cretin Priscilla Lopes Elodie Vimont Takashi Tatsuta Thomas Langer Anastasia Gazi Martin Sachse Patrick Yu‐Wai‐Man Pascal Reynier Timothy Wai |
| author_sort | Emma Cretin |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0f7ab26593fd4ea9a7b36b1989bf8ee6 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-0f7ab26593fd4ea9a7b36b1989bf8ee62025-08-20T04:03:06ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-05-0113612910.15252/emmm.202013579High‐throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblastsEmma Cretin0Priscilla Lopes1Elodie Vimont2Takashi Tatsuta3Thomas Langer4Anastasia Gazi5Martin Sachse6Patrick Yu‐Wai‐Man7Pascal Reynier8Timothy Wai9Mitochondrial Biology Group, Institut Pasteur, CNRS UMR 3691Mitochondrial Biology Group, Institut Pasteur, CNRS UMR 3691Mitochondrial Biology Group, Institut Pasteur, CNRS UMR 3691Max‐Planck‐Institute for Biology of AgeingMax‐Planck‐Institute for Biology of AgeingUTechS Ultrastructural Bio Imaging, Institut PasteurUTechS Ultrastructural Bio Imaging, Institut PasteurCambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of CambridgeLaboratoire de Biochimie et biologie moléculaire, Centre Hospitalier UniversitaireMitochondrial Biology Group, Institut Pasteur, CNRS UMR 3691Abstract 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.https://doi.org/10.15252/emmm.202013579genetic modifiershigh‐throughput screeningmitochondrial dynamicsOPA1phospholipid metabolism |
| spellingShingle | Emma Cretin Priscilla Lopes Elodie Vimont Takashi Tatsuta Thomas Langer Anastasia Gazi Martin Sachse Patrick Yu‐Wai‐Man Pascal Reynier Timothy Wai High‐throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts EMBO Molecular Medicine genetic modifiers high‐throughput screening mitochondrial dynamics OPA1 phospholipid metabolism |
| title | High‐throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts |
| title_full | High‐throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts |
| title_fullStr | High‐throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts |
| title_full_unstemmed | High‐throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts |
| title_short | High‐throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts |
| title_sort | high throughput screening identifies suppressors of mitochondrial fragmentation in opa1 fibroblasts |
| topic | genetic modifiers high‐throughput screening mitochondrial dynamics OPA1 phospholipid metabolism |
| url | https://doi.org/10.15252/emmm.202013579 |
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