Journal
MOLECULAR CELL
Volume 58, Issue 6, Pages 1001-1014Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2015.04.020
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Funding
- Agence Nationale de Recherche (ANR)
- Ligue contre le Cancer
- Region Ile-de-France (DIM STEM-Pole)
- University Paris Sud
- Association Francaise contre les Maladies Mitochondriales
- Swedish Research Council
- Swedish Childhood Cancer Foundation
- Frimurare Barnhus Foundation
- Swedish governmental grants
- Wilhelm and Martina Lundgren Foundation
- National Nature Science Foundation of China
- FIRB MERIT [RBNE08NKH7_003]
- Italian Ministry of University and Research (PRIN)
- EU grant
- Italian Ministry of Health
- NATIXIS
- UK Royal Society
- Scottish Universities Life Science Association (SULSA)
- Wellcome Trust
- National Strategic Reference Framework (NSRF):THALES
- Greek General Secretariat for Research and Technology Program ARISTEIA
- ERA-Net for Research on Rare Diseases
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- Institut National du Cancer (INCa)
- Fondation Bettencourt-Schueller
- Fondation de France
- Fondation pour la Recherche Medicale (FRM)
- European Commission (ArtForce)
- European Research Council (ERC)
- LabEx Immuno-Oncology
- Paris Alliance of Cancer Research Institutes (PACRI)
- Italian Ministry of University and Research (FIRB Accordi di Programma)
- AIRC
- European Union (European Social Fund-ESF)
- Operational Program Education and Lifelong Learning'' of the National Strategic Reference Framework (NSRF): THALES
- Operational Program Education and Lifelong Learning'' of the National Strategic Reference Framework (NSRF): Greek General Secretariat for Research and Technology Program ARISTEIA
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Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, beyond its apoptotic function, is required for the normal expression of major respiratory chain complexes. Here we identified an AIF-interacting protein, CHCHD4, which is the central component of a redox-sensitive mitochondrial intermembrane space import machinery. Depletion or hypomorphic mutation of AIF caused a downregulation of CHCHD4 protein by diminishing its mitochondrial import. CHCHD4 depletion sufficed to induce a respiratory defect that mimicked that observed in AIF-deficient cells. CHCHD4 levels could be restored in AIF-deficient cells by enforcing its AIF-independent mitochondrial localization. This modified CHCHD4 protein reestablished respiratory function in AIF-deficient cells and enabled AIF-deficient embryoid bodies to undergo cavitation, a process of programmed cell death required for embryonic morphogenesis. These findings explain how AIF contributes to the biogenesis of respiratory chain complexes, and they establish an unexpected link between the vital function of AIF and the propensity of cells to undergo apoptosis.
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