AIF deficiency compromises oxidative phosphorylation.
Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, after apoptosis induction, translocates to the nucleus where it participates in apoptotic chromatinolysis. Here, we show that human or mouse cells lacking AIF as a result of homologous recombination or small interfering RNA exhibit high lactate production and enhanced dependency on glycolytic ATP generation, due to severe reduction of respiratory chain complex I activity. Although AIF itself is not a part of complex I, AIF-deficient cells exhibit a reduced content of complex I and of its components, pointing to a role of AIF in the biogenesis and/or maintenance of this polyprotein complex. Harlequin mice with reduced AIF expression due to a retroviral insertion into the AIF gene also manifest a reduced oxidative phosphorylation (OXPHOS) in the retina and in the brain, correlating with reduced expression of complex I subunits, retinal degeneration, and neuronal defects. Altogether, these data point to a role of AIF in OXPHOS and emphasize the dual role of AIF in life and death.
Vahsen
Nicola
N
CNRS-UMR8125, Institut Gustave Roussy, Villejuif, France.
Candé
Céline
C
Brière
Jean-Jacques
JJ
Bénit
Paule
P
Joza
Nicholas
N
Larochette
Nathanael
N
Mastroberardino
Pier Giorgio
PG
Pequignot
Marie O
MO
Casares
Noelia
N
Lazar
Vladimir
V
Feraud
Olivier
O
Debili
Najet
N
Wissing
Silke
S
Engelhardt
Silvia
S
Madeo
Frank
F
Piacentini
Mauro
M
Penninger
Josef M
JM
Schägger
Hermann
H
Rustin
Pierre
P
Kroemer
Guido
G
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D042967:Electron Transport Complex I / Q000096:biosynthesis; D014450:Electron Transport Complex III / Q000096:biosynthesis; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000096:biosynthesis; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity; D010085:Oxidative Phosphorylation; D010802:Phylogeny; D034741:RNA, Small Interfering / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D015003:Yeasts / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D008565:Membrane Proteins; C494830:AIFM1 protein, mouse; D034741:RNA, Small Interfering; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D005947:Glucose