Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis

• 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.

Subject headings

NATURVETENSKAP  -- Biologi -- Cellbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Cell Biology (hsv//eng)

Keyword

Amino Acid Sequence

Animals

Apoptosis Inducing Factor

genetics

metabolism

Cell Line

Tumor

Electron Transport

genetics

Electron Transport Chain Complex Proteins

genetics

metabolism

Embryo

Mammalian

embryology

metabolism

Embryonic Development

genetics

Humans

Immunoblotting

Mice

Knockout

Mitochondria

genetics

metabolism

Mitochondrial Membrane Transport Proteins

genetics

metabolism

Molecular Sequence Data

Protein Binding

Protein Transport

genetics

RNA Interference

Time Factors

Publication and Content Type

ref (subject category)

art (subject category)