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Knockdown of APOPT1/COA8 Causes Cytochrome c Oxidase Deficiency, Neuromuscular Impairment, and Reduced Resistance to Oxidative Stress in Drosophila melanogaster
- Source :
- Frontiers in Physiology, Vol 10 (2019)
- Publication Year :
- 2019
- Publisher :
- Frontiers Media SA, 2019.
-
Abstract
- Cytochrome c oxidase (COX) deficiency is the biochemical hallmark of several mitochondrial disorders, including subjects affected by mutations in apoptogenic-1 (APOPT1), recently renamed as COA8 (HGNC:20492). Loss-of-function mutations are responsible for a specific infantile or childhood-onset mitochondrial leukoencephalopathy with a chronic clinical course. Patients deficient in COA8 show specific COX deficiency with distinctive neuroimaging features, i.e., cavitating leukodystrophy. In human cells, COA8 is rapidly degraded by the ubiquitin-proteasome system, but oxidative stress stabilizes the protein, which is then involved in COX assembly, possibly by protecting the complex from oxidative damage. However, its precise function remains unknown. The CG14806 gene (dCOA8) is the Drosophila melanogaster ortholog of human COA8 encoding a highly conserved COA8 protein. We report that dCOA8 knockdown (KD) flies show locomotor defects, and other signs of neurological impairment, reduced COX enzymatic activity, and reduced lifespan under oxidative stress conditions. Our data indicate that KD of dCOA8 in Drosophila phenocopies several features of the human disease, thus being a suitable model to characterize the molecular function/s of this protein in vivo and the pathogenic mechanisms associated with its defects.
- Subjects :
- 0301 basic medicine
Physiology
Mitochondrial disease
medicine.disease_cause
lcsh:Physiology
03 medical and health sciences
0302 clinical medicine
Physiology (medical)
medicine
Cytochrome c oxidase
APOPT1
Drosophila melanogaster
cytochrome c oxidase deficiency
knockdown models
mitochondrial disease
resistance to oxidative stress
Gene
chemistry.chemical_classification
Phenocopy
Gene knockdown
biology
lcsh:QP1-981
medicine.disease
biology.organism_classification
Cell biology
030104 developmental biology
Enzyme
chemistry
biology.protein
APOPT1, Drosophila melanogaster, cytochrome c oxidase deficiency, mitochondrial disease, resistance to oxidative stress, knockdown models
030217 neurology & neurosurgery
Oxidative stress
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Frontiers in Physiology, Vol 10 (2019)
- Accession number :
- edsair.doi.dedup.....2e430e0a4a1f1ae8942bd6b11cb32d36