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

Autor: Elizabeth C. Hinchy, Raffaele Cerutti, Rosalba Carrozzo, James A. Nathan, Erika Fernandez-Vizarra, Michael P. Murphy, Carlo Viscomi, Alba Signes, Daniele Ghezzi, Cristiane Benincá, Massimo Zeviani, Anna S Dickson, Enrico Bertini
Přispěvatelé: Ghezzi, Daniele [0000-0002-9358-1566], Bertini, Enrico [0000-0001-9276-4590], Nathan, James A [0000-0002-0248-1632], Viscomi, Carlo [0000-0001-6050-0566], Fernandez-Vizarra, Erika [0000-0002-2469-142X], Zeviani, Massimo [0000-0002-9067-5508], Apollo - University of Cambridge Repository
Rok vydání: 2018
Předmět:
0301 basic medicine
Medicine (General)
APOPT1-COA8
QH426-470
medicine.disease_cause
APOPT1‐COA8
Mice
0302 clinical medicine
cytochrome c oxidase
Cells
Cultured
Research Articles
chemistry.chemical_classification
Mice
Knockout
reactive oxygen species
Oxidase test
mitochondrial encephalopathy
proteasome–ubiquitin system
Animals
Apoptosis Regulatory Proteins
Electron Transport Complex IV
Genetic Complementation Test
Humans
Mitochondrial Proteins
Reactive Oxygen Species
Protein Multimerization
Unfolded Protein Response
Cultured
biology
Chemistry
Cell biology
Knockout mouse
Molecular Medicine
Research Article
Cells
Knockout
03 medical and health sciences
R5-920
Genetics
medicine
Cytochrome c oxidase
Gene
Reactive oxygen species
030104 developmental biology
Apoptosis
biology.protein
Genetics
Gene Therapy & Genetic Disease
030217 neurology & neurosurgery
Function (biology)
Oxidative stress
Zdroj: EMBO Molecular Medicine
EMBO Molecular Medicine, Vol 11, Iss 1, Pp n/a-n/a (2019)
ISSN: 1757-4684
Popis: 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.
Databáze: OpenAIRE
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