OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion.

Simple item page
dc.catalogadorgjm
dc.contributor.authorCartes Saavedra, Benjamín Tomás
dc.contributor.authorLagos Quiñones, Daniel Alejandro
dc.contributor.authorMacuada, Josefa
dc.contributor.authorArancibia Radich, Duxan Andrés
dc.contributor.authorBurté, Florence
dc.contributor.authorSjoberg, Marcela K.
dc.contributor.authorAndrés Coke, María Estela
dc.contributor.authorHorvath, Rita
dc.contributor.authorYu-Wai-Man, Patrick
dc.contributor.authorHajnoczky, Gyorgy
dc.contributor.authorEisner Sagüés, Verónica Raquel
dc.date.accessioned2024-01-30T15:23:30Z
dc.date.available2024-01-30T15:23:30Z
dc.date.issued2023
dc.description.abstractInner mitochondrial membrane fusion and cristae shape depend on optic atrophy protein 1, OPA1. Mutations in OPA1 lead to autosomal dominant optic atrophy (ADOA), an important cause of inherited blindness. The Guanosin Triphosphatase (GTPase) and GTPase effector domains (GEDs) of OPA1 are essential for mitochondrial fusion; yet, their specific roles remain elusive. Intriguingly, patients carrying OPA1 GTPase mutations have a higher risk of developing more severe multisystemic symptoms in addition to optic atrophy, suggesting pathogenic contributions for the GTPase and GED domains, respectively. We studied OPA1 GTPase and GED mutations to understand their domain-specific contribution to protein function by analyzing patient-derived cells and gain-of-function paradigms. Mitochondria from OPA1 GTPase (c.870+5G>A and c.889C>T) and GED (c.2713C>T and c.2818+5G>A) mutants display distinct aberrant cristae ultrastructure. While all OPA1 mutants inhibited mitochondrial fusion, some GTPase mutants resulted in elongated mitochondria, suggesting fission inhibition. We show that the GED is dispensable for fusion and OPA1 oligomer formation but necessary for GTPase activity. Finally, splicing defect mutants displayed a posttranslational haploinsufficiency-like phenotype but retained domain-specific dysfunctions. Thus, OPA1 domain-specific mutants result in distinct impairments in mitochondrial dynamics, providing insight into OPA1 function and its contribution to ADOA pathogenesis and severity.
dc.fechaingreso.objetodigital2024-06-04
dc.fuente.origenORCID
dc.identifier.doi10.1073/pnas.2207471120
dc.identifier.urihttps://doi.org/10.1073/pnas.2207471120
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/81061
dc.identifier.wosidWOS:000959773200006
dc.information.autorucFacultad de Ciencias Biológicas; Cartes Saavedra, Benjamín Tomás; 0000-0002-2753-5780; 186678
dc.information.autorucFacultad de Ciencias Biológicas; Lagos Quiñones, Daniel Alejandro; 0000-0003-2609-5397; 1070753
dc.information.autorucFacultad de Ciencias Biológicas; Macuada, Josefa; 0000-0001-7310-2233; 247431
dc.information.autorucFacultad de Ciencias Biológicas; Arancibia Radich, Duxan Andrés; 0000-0003-4423-5429; 250241
dc.information.autorucFacultad de Ciencias Biológicas; Sjoberg, Marcela K.; 0000-0001-7173-048X; 1040445
dc.information.autorucFacultad de Ciencias Biológicas; Andrés Coke, María Estela; 0000-0002-2078-2770; 74858
dc.information.autorucFacultad de Ciencias Biológicas; Eisner Sagüés, Verónica Raquel; 0000-0002-9458-7150; 238175
dc.language.isoen
dc.nota.accesoContenido completo
dc.rightsacceso abierto
dc.subject.ddc570
dc.subject.deweyBiologíaes_ES
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.titleOPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion.
dc.typeartículo
sipa.codpersvinculados186678
sipa.codpersvinculados1070753
sipa.codpersvinculados247431
sipa.codpersvinculados250241
sipa.codpersvinculados1040445
sipa.codpersvinculados74858
sipa.codpersvinculados238175
sipa.trazabilidadORCID;2024-01-15
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
OPA1 disease.pdf
Size:
3.97 MB
Format:
Adobe Portable Document Format
Description:
Download
Collections
Artículos de revistas