PUBLICATION
Novel in vivo models of autosomal optic atrophy reveal conserved pathological changes in neuronal mitochondrial structure and function
- Authors
- Strachan, E.L., Dillon, E.T., Sullivan, M., Glennon, J.C., Peyrel, A., Sarniguet, J., Dubois, K., Delprat, B., Kennedy, B.N., O'Sullivan, N.C.
- ID
- ZDB-PUB-250410-7
- Date
- 2025
- Source
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology 39: e70497e70497 (Journal)
- Registered Authors
- Kennedy, Breandan N.
- Keywords
- Drosophila, mitochondria, optic atrophy, visual impairment, zebrafish
- MeSH Terms
-
- Disease Models, Animal
- Zebrafish
- Drosophila melanogaster
- Optic Atrophy, Autosomal Dominant*/genetics
- Optic Atrophy, Autosomal Dominant*/metabolism
- Optic Atrophy, Autosomal Dominant*/pathology
- Retinal Ganglion Cells*/metabolism
- Retinal Ganglion Cells*/pathology
- Mitochondria*/metabolism
- Mitochondria*/pathology
- GTP Phosphohydrolases*/genetics
- GTP Phosphohydrolases*/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Neurons/metabolism
- Neurons/pathology
- Animals
- PubMed
- 40202868 Full text @ FASEB J.
Citation
Strachan, E.L., Dillon, E.T., Sullivan, M., Glennon, J.C., Peyrel, A., Sarniguet, J., Dubois, K., Delprat, B., Kennedy, B.N., O'Sullivan, N.C. (2025) Novel in vivo models of autosomal optic atrophy reveal conserved pathological changes in neuronal mitochondrial structure and function. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 39:e70497e70497.
Abstract
Autosomal optic atrophy (AOA) is a form of hereditary optic neuropathy characterized by the irreversible and progressive degermation of the retinal ganglion cells. Most cases of AOA are associated with a single dominant mutation in OPA1, which encodes a protein required for fusion of the inner mitochondrial membrane. It is unclear how loss of OPA1 leads to neuronal death, and despite ubiquitous expression appears to disproportionately affect the RGCs. This study introduces two novel in vivo models of OPA1-mediated AOA, including the first developmentally viable vertebrate Opa1 knockout (KO). These models allow for the study of Opa1 loss in neurons, specifically RGCs. Though survival is significantly reduced in Opa1 deficient zebrafish and Drosophila, both models permit the study of viable larvae. Moreover, zebrafish Opa1 KO larvae show impaired visual function but unchanged locomotor function, indicating that retinal neurons are particularly sensitive to Opa1 loss. Proteomic profiling of both models reveals marked disruption in protein expression associated with mitochondrial function, consistent with an observed decrease in mitochondrial respiratory function. Similarly, mitochondrial fragmentation and disordered cristae organization were observed in neuronal axons in both models highlighting Opa1's highly conserved role in regulating mitochondrial morphology and function in neuronal axons. Importantly, in Opa1 deficient zebrafish, mitochondrial disruption and visual impairment precede degeneration of RGCs. These novel models mimic key features of AOA and provide valuable tools for therapeutic screening. Our findings suggest that therapies enhancing mitochondrial function may offer a potential treatment strategy for AOA.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping