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Lookup NU author(s): Dr Patrick Yu Wai Man, Professor Rita HorvathORCiD, Dr Tim RudgeORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024. Optic 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 led 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+5 G > A or c.2713 C > T in WT cells, showed perturbed nucleoid array in the mitochondria population associated with cristae disorganization, which was partly reproduced in Skeletal muscle-derived fibroblasts from ADOA patients harboring the same mutants. 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.
Author(s): Macuada J, Molina-Riquelme I, Vidal G, Perez-Bravo N, Vasquez-Trincado C, Aedo G, Lagos D, Yu-Wai-Man P, Horvath R, Rudge TJ, Cartes-Saavedra B, Eisner V
Publication type: Article
Publication status: Published
Journal: Cell Death and Disease
Year: 2024
Volume: 15
Issue: 11
Online publication date: 30/11/2024
Acceptance date: 17/10/2024
Date deposited: 17/12/2024
ISSN (electronic): 2041-4889
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41419-024-07165-9
DOI: 10.1038/s41419-024-07165-9
Data Access Statement: The MiNuD Python package is openly available in GitHub and can be found in (https://github.com/RudgeLab/MiNuD). The data that support the findings in this paper can be found in Supplementary Materials. Any further data can be provided after reasonable request to the corresponding author.
PubMed id: 39616197
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