Muscle-Specific Loss of Apoptosis-Inducing Factor Leads to Mitochondrial Dysfunction, Skeletal Muscle Atrophy, and Dilated Cardiomyopathy

Abstract

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 AIFregulated 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.In animals, the growth and maintenance of tissues absolutely depend on energy metabolism, which is met principally through mitochondrial oxidative phosphorylation (OXPHOS). OXPHOS is a complex biochemical process in which electrons generated from the catabolism of energy substrates flow through a series of catalysts known as the mitochondrial respiratory chain; the free energy liberated from this oxidative process drives formation of an electrochemical potential difference across the inner mitochondrial membrane which is utilized to generate energy for the cell in the form of ATP.

Response of caspase-independent apoptotic factors to high salt diet-induced heart failure

“…Deletion of AIF by homologous recombination or the suppression of AIF expression by siRNA resulted in high lactate production and increased dependency on the glycolytic energy generating process due to a remarkable reduction of respiratory chain complex I activity [7] [24]. Joza et al showed that animals that were cardiac and skeletal muscle-specifically deficient in AIF developed severe dilated cardiomyopathy, heart failure, and skeletal atrophy accompanied by impaired activity and protein expression of respiratory chain complex I, defective mitochondrial respiratory function, a metabolic switch toward glucose metabolism, and lactic acidosis.…”

“…With respect to the caspase-independent pathway, a cluster of cellular factors including apoptosis-inducing factor (AIF), endonuclease G (EndoG) and high temperature requirement protein A2 (HtrA2/Omi) have been shown to be able to induce apoptosis without the mediation of the caspases, the central apoptosis executing proteases [4][5][6]. Some suggest that AIF, a mitochondrial flavoprotein, has both oxidoreductase and apoptosis-inducing activities [7]. Although its precise physiologic functions are unclear, the apoptotic character of AIF has been well demonstrated and it is believed that its apoptotic trait might be attributable to a putative DNA binding site responsible for chromatin condensation and DNA fragmentation [8].…”

Mitochondrial dynamics in the regulation of neuronal cell death

“…Hence increase in nNOS activity is moderate and less ROS is produced role in mitochondria. AIF deficient cells emphasize the importance of AIF in maintaining mitochondrial function since these cells exhibit a loss of complex 1 stability and activity, and disruption of oxidative phosphorylation [143,144]. In order to separate the function of the mitochondrial AIF from the nuclear functions of AIF during cell death, we constructed anchored AIF mutants which are anchored in the inner membrane of mitochondria and cannot be released during apoptosis.…”

Insulinorésistance et fonction mitochondriale

“…Un paradoxe inattendu : hypersensibilité à l'insuline lors d'un défaut de phosphorylation oxydative mitochondriale Les travaux précédents du laboratoire de J. Penninger en Autriche ont montré que la délétion génique d'une protéine mitochondriale impliquée dans le contrôle de l'apoptose, AIF (apoptosis inducing factor), induisait la réduction progressive des capacités de phosphorylation oxydative de la mitochondrie chez la souris [9,10]. Ainsi, en collaboration avec A. Pospisilik de son laboratoire, nous avons utilisé cette caractéristique pour démontrer la causalité moléculaire et fonctionnelle du rôle de la phosphorylation oxydative mitochondriale dans le développement de l'insulino-résistance [11].…”