APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS.
Hinchy, Elizabeth C
EMBO molecular medicine
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Signes, A., Cerutti, R., Dickson, A., Benincá, C., Hinchy, E. C., Ghezzi, D., Carrozzo, R., et al. (2019). APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS.. EMBO molecular medicine, 11 (1)https://doi.org/10.15252/emmm.201809582
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 intra-mitochondrial form and thereby protecting COX from oxidatively-induced degradation.
Cells, Cultured, Animals, Mice, Knockout, Humans, Mice, Reactive Oxygen Species, Electron Transport Complex IV, Mitochondrial Proteins, Genetic Complementation Test, Apoptosis Regulatory Proteins, Protein Multimerization, Unfolded Protein Response
Wellcome Trust (102770/Z/13/Z)
Lister Institute of Preventive Medicine (unknown)
Wellcome Trust (110159/Z/15/Z)
European Commission FP7 ERC Advanced Investigator Grants (AIG) (322424)
External DOI: https://doi.org/10.15252/emmm.201809582
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287402
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/