OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution
Abstract 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, bioenerg...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07165-9 |
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| author | J. Macuada I. Molina-Riquelme G. Vidal N. Pérez-Bravo C. Vásquez-Trincado G. Aedo D. Lagos P. Yu-Wai-Man R. Horvath T. J. Rudge B. Cartes-Saavedra V. Eisner |
| author_facet | J. Macuada I. Molina-Riquelme G. Vidal N. Pérez-Bravo C. Vásquez-Trincado G. Aedo D. Lagos P. Yu-Wai-Man R. Horvath T. J. Rudge B. Cartes-Saavedra V. Eisner |
| author_sort | J. Macuada |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-fde6a90279e94de0badf99ed7309880a |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-fde6a90279e94de0badf99ed7309880a2025-08-20T02:38:35ZengNature Publishing GroupCell Death and Disease2041-48892024-11-01151111010.1038/s41419-024-07165-9OPA1 and disease-causing mutants perturb mitochondrial nucleoid distributionJ. Macuada0I. Molina-Riquelme1G. Vidal2N. Pérez-Bravo3C. Vásquez-Trincado4G. Aedo5D. Lagos6P. Yu-Wai-Man7R. Horvath8T. J. Rudge9B. Cartes-Saavedra10V. Eisner11Facultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileFacultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileInstitute for Biological and Medical Engineering, Schools of Engineering, Biology, and Medicine, Pontificia Universidad Católica de ChileFacultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileFacultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileFacultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileFacultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileDepartment of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of CambridgeDepartment of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of CambridgeInstitute for Biological and Medical Engineering, Schools of Engineering, Biology, and Medicine, Pontificia Universidad Católica de ChileFacultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileFacultad de Ciencias Biológicas, Pontificia Universidad Católica de ChileAbstract 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.https://doi.org/10.1038/s41419-024-07165-9 |
| spellingShingle | J. Macuada I. Molina-Riquelme G. Vidal N. Pérez-Bravo C. Vásquez-Trincado G. Aedo D. Lagos P. Yu-Wai-Man R. Horvath T. J. Rudge B. Cartes-Saavedra V. Eisner OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution Cell Death and Disease |
| title | OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution |
| title_full | OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution |
| title_fullStr | OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution |
| title_full_unstemmed | OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution |
| title_short | OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution |
| title_sort | opa1 and disease causing mutants perturb mitochondrial nucleoid distribution |
| url | https://doi.org/10.1038/s41419-024-07165-9 |
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