APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS.

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Signes, Alba 
Cerutti, Raffaele 
Dickson, Anna S 
Benincá, Cristiane 
Hinchy, Elizabeth C 

Loss-of-function mutations in APOPT1, a gene exclusively found in higher eukaryotes, cause a characteristic type of cavitating leukoencephalopathy associated with mitochondrial cytochrome c oxidase (COX) deficiency. Although the genetic association of APOPT1 pathogenic variants with isolated COX defects is now clear, the biochemical link between APOPT1 function and COX has remained elusive. We investigated the molecular role of APOPT1 using different approaches. First, we generated an Apopt1 knockout mouse model which shows impaired motor skills, e.g., decreased motor coordination and endurance, associated with reduced COX activity and levels in multiple tissues. In addition, by achieving stable expression of wild-type APOPT1 in control and patient-derived cultured cells we ruled out a role of this protein in apoptosis and established instead that this protein is necessary for proper COX assembly and function. On the other hand, APOPT1 steady-state levels were shown to be controlled by the ubiquitination-proteasome system (UPS). Conversely, in conditions of increased oxidative stress, APOPT1 is stabilized, increasing its mature intramitochondrial form and thereby protecting COX from oxidatively induced degradation.

APOPT1‐COA8, cytochrome c oxidase, mitochondrial encephalopathy, proteasome–ubiquitin system, reactive oxygen species, Animals, Apoptosis Regulatory Proteins, Cells, Cultured, Electron Transport Complex IV, Genetic Complementation Test, Humans, Mice, Mice, Knockout, Mitochondrial Proteins, Protein Multimerization, Reactive Oxygen Species, Unfolded Protein Response
Journal Title
EMBO Mol Med
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Volume Title
Medical Research Council (MC_UP_1002/1)
Wellcome Trust (102770/Z/13/Z)
Lister Institute of Preventive Medicine (unknown)
Medical Research Council (MC_UU_00015/3)
Wellcome Trust (110159/Z/15/Z)
MRC (MC_UP_1002/1)
Medical Research Council (MC_UU_00015/8)
European Research Council (322424)
MRC (MC_UU_00015/8)