Mitochondrial AIF loss causes metabolic reprogramming, caspase-independent cell death blockade, embryonic lethality, and perinatal hydrocephalus.
Animals
Apoptosis
/ physiology
Apoptosis Inducing Factor
/ genetics
Caspases
/ metabolism
Cell Respiration
Female
Fibroblasts
/ metabolism
Genetic Engineering
/ methods
Glycolysis
/ genetics
Hydrocephalus
/ metabolism
Male
Membrane Potential, Mitochondrial
/ genetics
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
/ genetics
Mitochondria
/ metabolism
Models, Animal
Oxidative Phosphorylation
Reactive Oxygen Species
/ metabolism
AIF
Caspase-independent cell death
Hydrocephaly
Metabolism
Mitochondria
OXPHOS
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
04
03
2020
revised:
18
05
2020
accepted:
27
05
2020
pubmed:
2
6
2020
medline:
9
7
2021
entrez:
2
6
2020
Statut:
ppublish
Résumé
Apoptosis-Inducing Factor (AIF) is a protein involved in mitochondrial electron transport chain assembly/stability and programmed cell death. The relevant role of this protein is underlined because mutations altering mitochondrial AIF properties result in acute pediatric mitochondriopathies and tumor metastasis. By generating an original AIF-deficient mouse strain, this study attempted to analyze, in a single paradigm, the cellular and developmental metabolic consequences of AIF loss and the subsequent oxidative phosphorylation (OXPHOS) dysfunction. We developed a novel AIF-deficient mouse strain and assessed, using molecular and cell biology approaches, the cellular, embryonic, and adult mice phenotypic alterations. Additionally, we conducted ex vivo assays with primary and immortalized AIF knockout mouse embryonic fibroblasts (MEFs) to establish the cell death characteristics and the metabolic adaptive responses provoked by the mitochondrial electron transport chain (ETC) breakdown. AIF deficiency destabilized mitochondrial ETC and provoked supercomplex disorganization, mitochondrial transmembrane potential loss, and high generation of mitochondrial reactive oxygen species (ROS). AIF In a single knockout model and at 3 different levels (cell, embryo, and adult mice) we demonstrated that by controlling the mitochondrial OXPHOS/metabolism, AIF is a key factor regulating cell differentiation and fate. Additionally, by providing new insights into the pathological consequences of mitochondrial OXPHOS dysfunction, our new findings pave the way for novel pharmacological strategies.
Identifiants
pubmed: 32480041
pii: S2212-8778(20)30101-0
doi: 10.1016/j.molmet.2020.101027
pmc: PMC7334469
pii:
doi:
Substances chimiques
Apoptosis Inducing Factor
0
AIFM1 protein, mouse
0
Reactive Oxygen Species
0
Caspases
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101027Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.
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