AUTHOR=Brischigliaro Michele , Corrà Samantha , Tregnago Claudia , Fernandez-Vizarra Erika , Zeviani Massimo , Costa Rodolfo , De Pittà Cristiano 

TITLE=Knockdown of APOPT1/COA8 Causes Cytochrome c Oxidase Deficiency, Neuromuscular Impairment, and Reduced Resistance to Oxidative Stress in Drosophila melanogaster

JOURNAL=Frontiers in Physiology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2019.01143

DOI=10.3389/fphys.2019.01143

ISSN=1664-042X

ABSTRACT=<p>Cytochrome <italic>c</italic> oxidase (COX) deficiency is the biochemical hallmark of several mitochondrial disorders, including subjects affected by mutations in <italic>apoptogenic-1</italic> (<italic>APOPT1</italic>), recently renamed as <italic>COA8</italic> (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 <italic>CG14806</italic> gene (<italic>dCOA8</italic>) is the <italic>Drosophila melanogaster</italic> ortholog of human <italic>COA8</italic> encoding a highly conserved COA8 protein. We report that <italic>dCOA8</italic> 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 <italic>dCOA8</italic> in <italic>Drosophila</italic> phenocopies several features of the human disease, thus being a suitable model to characterize the molecular function/s of this protein <italic>in vivo</italic> and the pathogenic mechanisms associated with its defects.</p>