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

Research output: Contribution to journalArticle

Abstract

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
DOIs
Publication statusE-pub ahead of print - Dec 14 2018

Fingerprint

Ubiquitination
Proteasome Endopeptidase Complex
Oxidoreductases
Cytochrome-c Oxidase Deficiency
Leukoencephalopathies
Motor Skills
Eukaryota
Knockout Mice
Cultured Cells
Proteins
Oxidative Stress
Apoptosis
Mutation
Genes

Cite this

Signes, A., Cerutti, R., Dickson, A. S., Benincá, C., Hinchy, E. C., Ghezzi, D., ... 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

APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS. / 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; Fernandez-Vizarra, Erika; Zeviani, Massimo.

In: EMBO Molecular Medicine, 14.12.2018.

Research output: Contribution to journalArticle

Signes, A, Cerutti, R, Dickson, AS, Benincá, C, Hinchy, EC, Ghezzi, D, Carrozzo, R, Bertini, E, Murphy, MP, Nathan, JA, 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
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 ; Fernandez-Vizarra, Erika ; Zeviani, Massimo. / APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS. In: EMBO Molecular Medicine. 2018.
@article{83625bc11fe2400eace6ad5159916741,
title = "APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS",
abstract = "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.",
author = "Alba Signes and Raffaele Cerutti and Dickson, {Anna S} and Cristiane Beninc{\'a} and Hinchy, {Elizabeth C} and Daniele Ghezzi and Rosalba Carrozzo and Enrico Bertini and Murphy, {Michael P} and Nathan, {James A} and Carlo Viscomi and Erika Fernandez-Vizarra and Massimo Zeviani",
note = "{\circledC} 2018 The Authors. Published under the terms of the CC BY 4.0 license.",
year = "2018",
month = "12",
day = "14",
doi = "10.15252/emmm.201809582",
language = "English",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS

AU - Signes, Alba

AU - Cerutti, Raffaele

AU - Dickson, Anna S

AU - Benincá, Cristiane

AU - Hinchy, Elizabeth C

AU - Ghezzi, Daniele

AU - Carrozzo, Rosalba

AU - Bertini, Enrico

AU - Murphy, Michael P

AU - Nathan, James A

AU - Viscomi, Carlo

AU - Fernandez-Vizarra, Erika

AU - Zeviani, Massimo

N1 - © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2018/12/14

Y1 - 2018/12/14

N2 - 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.

AB - 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.

U2 - 10.15252/emmm.201809582

DO - 10.15252/emmm.201809582

M3 - Article

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

ER -