Open AccessAPOPT 1/ COA 8 assists COX assembly and is oppositely regulated by UPS and ROS
Author(s) -
Signes Alba,
Cerutti Raffaele,
Dickson Anna S,
Benincá Cristiane,
Hinchy Elizabeth C,
Ghezzi Daniele,
Carrozzo Rosalba,
Bertini Enrico,
Murphy Michael P,
Nathan James A,
Viscomi Carlo,
FernandezVizarra Erika,
Zeviani Massimo
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201809582
Subject(s) - microbiology and biotechnology , chemistry , function (biology) , oxidative stress , biochemistry , biology
Loss‐of‐function mutations in APOPT 1 , 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 APOPT 1 pathogenic variants with isolated COX defects is now clear, the biochemical link between APOPT 1 function and COX has remained elusive. We investigated the molecular role of APOPT 1 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 APOPT 1 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, APOPT 1 steady‐state levels were shown to be controlled by the ubiquitination–proteasome system ( UPS ). Conversely, in conditions of increased oxidative stress, APOPT 1 is stabilized, increasing its mature intramitochondrial form and thereby protecting COX from oxidatively induced degradation.