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

Alba Signes, Raffaele Cerutti, Anna S Dickson, Cristiane Benincá, Elizabeth C Hinchy, Daniele Ghezzi, Rosalba Carrozzo, Enrico Bertini, Michael P Murphy, James A Nathan, Carlo Viscomi, Erika Fernandez-Vizarra, Massimo Zeviani

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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.

Original languageEnglish
Number of pages21
JournalEMBO Molecular Medicine
Publication statusE-pub ahead of print - Dec 14 2018


Cite this

Signes, A., Cerutti, R., Dickson, A. S., Benincá, C., Hinchy, E. C., Ghezzi, D., Carrozzo, R., Bertini, E., Murphy, M. P., Nathan, J. A., Viscomi, C., Fernandez-Vizarra, E., & Zeviani, M. (2018). APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS. EMBO Molecular Medicine. https://doi.org/10.15252/emmm.201809582