Muscle-specific loss of apoptosis-inducing factor leads to mitochondrial dysfunction, skeletal muscle atrophy, and dilated cardiomyopathy.
Cardiac and skeletal muscle critically depend on mitochondrial energy metabolism for their normal function. Recently, we showed that apoptosis-inducing factor (AIF), a mitochondrial protein implicated in programmed cell death, plays a role in mitochondrial respiration. However, the in vivo consequences of AIF-regulated mitochondrial respiration resulting from a loss-of-function mutation in Aif are not known. Here, we report tissue-specific deletion of Aif in the mouse. Mice in which Aif has been inactivated specifically in cardiac and skeletal muscle exhibit impaired activity and protein expression of respiratory chain complex I. Mutant animals develop severe dilated cardiomyopathy, heart failure, and skeletal muscle atrophy accompanied by lactic acidemia consistent with defects in the mitochondrial respiratory chain. Isolated hearts from mutant animals exhibit poor contractile performance in response to a respiratory chain-dependent energy substrate, but not in response to glucose, supporting the notion that impaired heart function in mutant animals results from defective mitochondrial energy metabolism. These data provide genetic proof that the previously defined cell death promoter AIF has a second essential function in mitochondrial respiration and aerobic energy metabolism required for normal heart function and skeletal muscle homeostasis.
Joza
Nicholas
N
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3-5, 1030 Vienna, Austria. nicholas.joza@imba.oeaw.ac.at
Oudit
Gavin Y
GY
Brown
Doris
D
Bénit
Paule
P
Kassiri
Zamaneh
Z
Vahsen
Nicola
N
Benoit
Loralyn
L
Patel
Mikin M
MM
Nowikovsky
Karin
K
Vassault
Anne
A
Backx
Peter H
PH
Wada
Teiji
T
Kroemer
Guido
G
Rustin
Pierre
P
Penninger
Josef M
JM
D000818:Animals; D051033:Apoptosis Inducing Factor / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers; D002311:Cardiomyopathy, Dilated / Q000196:embryology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D009133:Muscular Atrophy / Q000196:embryology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress
D051033:Apoptosis Inducing Factor; D015415:Biomarkers; D005947:Glucose