OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution

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dc.catalogadoryvc
dc.contributor.authorMacuada Alvarado, Josefa Pilar
dc.contributor.authorMolina Riquelme, Isidora Elvira
dc.contributor.authorVidal, Gonzalo
dc.contributor.authorPérez Bravo, N.
dc.contributor.authorVásquez-Trincado, C.
dc.contributor.authorAedo, G.
dc.contributor.authorLagos, D.
dc.contributor.authorHorvath, R.
dc.contributor.authorRudge Timothy, James
dc.contributor.authorCartes Saavedra, Benjamín Tomas
dc.contributor.authorEisner Sagues, Verónica Raquel
dc.date.accessioned2024-05-08T02:10:59Z
dc.date.available2024-05-08T02:10:59Z
dc.date.issued2024
dc.descriptionThe copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
dc.description.abstractOptic atrophy protein 1 (OPA1) mediates inner mitochondrial membrane (IMM) fusion and cristae organization. Mutations in OPA1 cause autosomal dominant optic atrophy (ADOA), a leading cause of blindness. Cells from ADOA patients show impaired mitochondrial fusion, cristae structure, bioenergetic function, and mitochondrial DNA (mtDNA) integrity. The mtDNA encodes electron transport chain subunits and is packaged into nucleoids spread within the mitochondrial population. Nucleoids interact with the IMM, and their distribution is tightly linked to mitochondrial fusion and cristae shaping. Yet, little is known about the physio-pathological relevance of nucleoid distribution. We studied the effect of OPA1 and ADOA-associated mutants on nucleoid distribution using high-resolution confocal microscopy. We applied a novel model incorporating the mitochondrial context, separating nucleoid distribution into the array in the mitochondrial population and intramitochondrial longitudinal distribution. Opa1-null cells showed decreased mtDNA levels and nucleoid abundance. Also, loss of Opa1 lead to an altered distribution of nucleoids in the mitochondrial population, loss of cristae periodicity, and altered nucleoids to cristae proximity partly rescued by OPA1 isoform 1. Overexpression of WT OPA1 or ADOA-causing mutants c.870+5G>A or c.2713C>T in WT cells, showed perturbed nucleoid array in the mitochondria population associated with cristae disorganization. Opa1-null and cells overexpressing ADOA mutants accumulated mitochondria without nucleoids. Interestingly, intramitochondrial nucleoid distribution was only altered in Opa1-null cells. Altogether, our results highlight the relevance of OPA1 in nucleoid distribution in the mitochondrial landscape and at a single-organelle level and shed light on new components of ADOA etiology. The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
dc.fechaingreso.objetodigital2024-05-07
dc.fuente.origenORCID
dc.identifier.doi10.1101/2024.02.01.578418
dc.identifier.urihttps://doi.org/10.1101/2024.02.01.578418
dc.identifier.urihttp://www.scopus.com/inward/record.url?eid=2-s2.0-85188164564&partnerID=MN8TOARS
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/85496
dc.information.autorucFacultad de Ciencias Biológicas; Macuada Alvarado, Josefa Pilar; S/I; 247431
dc.information.autorucFacultad de Ciencias Biológicas; Molina Riquelme, Isidora Elvira; S/I; 1126907
dc.information.autorucInstituto de Ingeniería Biológica y Médica; Rudge Timothy, James; S/I; 1031921
dc.information.autorucFacultad de Ciencias Biológicas; Cartes Saavedra, Benjamín Tomas; S/I; 186678
dc.information.autorucFacultad de Ciencias Biológicas; Eisner Sagues, Verónica Raquel; 0000-0002-9458-7150; 238175
dc.language.isoen
dc.nota.accesocontenido completo
dc.rightsacceso restringido
dc.subjectCell biology
dc.subject.ddc570
dc.subject.deweyBiologíaes_ES
dc.titleOPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution
dc.typepreprint
sipa.codpersvinculados247431
sipa.codpersvinculados1126907
sipa.codpersvinculados1031921
sipa.codpersvinculados186678
sipa.codpersvinculados238175
sipa.trazabilidadORCID;2024-05-06
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