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OPA1 mutations associated with dominant optic atrophy affect mitochondrial fusion and cell death in a domain-specific manner

ABSTRACT: OPA1 mutations associated with dominant optic atrophy affect mitochondrial fusion and cell death in a domain-specific manner

PROVIDER: PRJNA1225147 | ENA |

REPOSITORIES: ENA

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OPA1 mutations associated with dominant optic atrophy affect mitochondrial fusion and cell death in a domain-specific manner

Project description:Our study uncovered the role of OPA1 BSE domain in modulation of mitochondrial dynamics and cell death, and characterized the related signaling pathways, hereby providing the insight into the understanding of the domain-specific effect of OPA1 on mitochondrial morphology and function.

2025-02-24 | GSE289826 | GEO

The mitochondrial fusion protein OPA1 is dispensable in the live

Project description:Mitochondria are critical for metabolic homeostasis of the liver, and thus, mitochondrial dysfunction is a major cause of liver diseases. Optic atrophy 1 (OPA1) is a mitochondrial fusion protein that also plays a role in cristae shaping. Hence, the OPA1 gene disruption has been shown to cause mitochondrial dysfunction. However, the role of OPA1 in liver function is poorly understood. In this study, we deleted OPA1 in fully developed mouse liver and examined its effect.

2023-10-30 | PXD040556 | Pride

Discovering genetic causes of optic atrophy syndromes through whole exome sequencing

Project description:The genetic defects leading to optic atrophy range from mitochondrial DNA (mtDNA) point mutations in LeberÃ¢Â€Â™s hereditary optic neuropathy (LHON), to dominant and recessive mutations affecting a cluster of nuclear genes implicated in mitochondrial dynamics. We performed WES in patients with an optic atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with mitochondrial DNA (mtDNA) depletion without accumulation of multiple deletions, to identify the genetic causes of this syndrome.

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Heart proteome in Cox10 depending on Opa1 processing

Project description:Mitochondrial fusion and fission accompany adaptive responses to stress and altered metabolic demands. Inner membrane fusion and cristae morphogenesis depends on Optic Atrophy 1 (Opa1), which is expressed in different isoforms and is cleaved from a membrane-bound, long to a soluble, short form. Here, we have analyzed the physiological role of Opa1 isoforms and Opa1 processing by generating mouse lines expressing only one cleavable Opa1 isoform or a non-cleavable variant thereof. Our results show that expression of a single cleavable or non-cleavable Opa1 isoform preserves embryonic development and the health of adult mice. Opa1 processing is dispensable under metabolic and thermal stress, but prolongs lifespan and protects against mitochondrial cardiomyopathy in OXPHOS-deficient Cox10-/- mice. Mechanistically, loss of Opa1 processing disturbs the balance between mitochondrial biogenesis and mitophagy, suppressing cardiac hypertrophic growth in Cox10-/- hearts. Our results highlight the critical regulatory role of Opa1 processing, mitochondrial dynamics and metabolism for cardiac hypertrophy.

2024-08-10 | PXD048804 | Pride

OPA1 Dominant Optic Atrophy: Pathogenesis and Therapeutic Targets

Project description: Not available

| S-EPMC10645107 | biostudies-literature

Transcriptome analysis in brown adipose tissue of mice lacking the mitochondrial protein optic atrophy 1 (OPA1) in thermogenic adipocytes

Project description:Transcriptome analysis in brown adipose tissue of mice lacking the mitochondrial protein optic atrophy 1 (OPA1) in thermogenic adipocytes

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Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy.

Project description:Optic Atrophy 1 (OPA1) gene mutations cause diseases ranging from isolated dominant optic atrophy (DOA) to various multisystemic disorders. OPA1, a large GTPase belonging to the dynamin family, is involved in mitochondrial network dynamics. The majority of OPA1 mutations encodes truncated forms of the protein and causes DOA through haploinsufficiency, whereas missense OPA1 mutations are predicted to cause disease through deleterious dominant-negative mechanisms. We used 3D imaging and biochemical analysis to explore autophagy and mitophagy in fibroblasts from seven patients harbouring OPA1 mutations. We report new genotype-phenotype correlations between various types of OPA1 mutation and mitophagy. Fibroblasts bearing dominant-negative OPA1 mutations showed increased autophagy and mitophagy in response to uncoupled oxidative phosphorylation. In contrast, OPA1 haploinsufficiency was correlated with a substantial reduction in mitochondrial turnover and autophagy, unless subjected to experimental mitochondrial injury. Our results indicate distinct alterations of mitochondrial physiology and turnover in cells with OPA1 mutations, suggesting that the level and profile of OPA1 may regulate the rate of mitophagy.

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Transcriptome analysis in brown adipose tissue of mice lacking the mitochondrial protein optic atrophy 1 (OPA1) in thermogenic adipocytes

Project description:mRNA expression profiles from interscapular brown adipose (iBAT) tissue of 7-week-old OPA1 BAT KO mice and their WT counterparts.

2023-10-10 | GSE218907 | GEO

Mitochondrial dysfunction in an Opa1(Q285STOP) mouse model of dominant optic atrophy results from Opa1 haploinsufficiency.

Project description:Mutations in the opa1 (optic atrophy 1) gene lead to autosomal dominant optic atrophy (ADOA), a hereditary eye disease. This gene encodes the Opa1 protein, a mitochondrial dynamin-related GTPase required for mitochondrial fusion and the maintenance of normal crista structure. The majority of opa1 mutations encode truncated forms of the protein, lacking a complete GTPase domain. It is unclear whether the phenotype results from haploinsufficiency or rather a deleterious effect of truncated Opa1 protein. We studied a heterozygous Opa1 mutant mouse carrying a defective allele with a stop codon in the beginning of the GTPase domain at residue 285, a mutation that mimics human pathological mutations. Using an antibody raised against an N-terminal portion of Opa1, we found that the level of wild-type protein was decreased in the mutant mice, as predicted. However, no truncated Opa1 protein was expressed. In embryonic fibroblasts isolated from the mutant mice, this partial loss of Opa1 caused mitochondrial respiratory deficiency and a selective loss of respiratory Complex IV subunits. Furthermore, partial Opa1 deficiency resulted in a substantial resistance to endoplasmic reticulum stress-induced death. On the other hand, the enforced expression of truncated Opa1 protein in cells containing normal levels of wild-type protein did not cause mitochondrial defects. Moreover, cells expressing the truncated Opa1 protein showed reduced Bax activation in response to apoptotic stimuli. Taken together, our results exclude deleterious dominant-negative or gain-of-function mechanisms for this type of Opa1 mutation and affirm haploinsufficiency as the mechanism underlying mitochondrial dysfunction in ADOA.

| S-EPMC4973340 | biostudies-literature

Genomic deletions in OPA1 in Danish patients with autosomal dominant optic atrophy.

Project description:BACKGROUND: Autosomal dominant optic atrophy (ADOA, Kjer disease, MIM #165500) is the most common form of hereditary optic neuropathy. Mutations in OPA1 located at chromosome 3q28 are the predominant cause for ADOA explaining between 32 and 89% of cases. Although deletions of OPA1 were recently reported in ADOA, the frequency of OPA1 genomic rearrangements in Denmark, where ADOA has a high prevalence, is unknown. The aim of the study was to identify copy number variations in OPA1 in Danish ADOA patients. METHODS: Forty unrelated ADOA patients, selected from a group of 100 ADOA patients as being negative for OPA1 point mutations, were tested for genomic rearrangements in OPA1 by multiplex ligation probe amplification (MLPA). When only one probe was abnormal results were confirmed by additional manually added probes. Segregation analysis was performed in families with detected mutations when possible. RESULTS: Ten families had OPA1 deletions, including two with deletions of the entire coding region and eight with intragenic deletions. Segregation analysis was possible in five families, and showed that the deletions segregated with the disease. CONCLUSION: Deletions in the OPA1 gene were found in 10 patients presenting with phenotypic autosomal dominant optic neuropathy. Genetic testing for deletions in OPA1 should be offered for patients with clinically diagnosed ADOA and no OPA1 mutations detected by DNA sequencing analysis.

| S-EPMC3079616 | biostudies-literature

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