The point mutation in the apoptosis inducing factor (AIF) gene causing early derangement in human brain development specifically alters the NADH reactivity of the flavoprotein

The apoptosis inducing factor (AIF) is a mitochondrial NAD(H)-binding flavoprotein that, when released from the organelle in response to various stimuli, causes cell death (1). In addition to its role in caspase-independent apoptosis, AIF also plays an essential, although poorly understood, function in maintaining the functionality of oxidative phosphorylation. While AIF gene inactivation is embryonic lethal in mammals, downregulation of its expression causes myopathies and neurological abnormalities (1). Very recently, two distinct point mutations in human AIF gene were identified as responsible of human mitochondriopathies resulting in severe early encephalomyopathy (2) and prenatal ventriculomegaly (3), respectively. We have reproduced the latter mutation in mouse AIF. The pathogenic AIF-G307E variant was isolated in a recombinant form and was shown to be as stable as the wild-type protein. This amino acyl replacement was found to significantly slow down the reaction between the protein and NADH that leads to the formation of a NAD+-FADH- charge-transfer complex, which has been previously shown to be linked to a monomer-dimer transition of the protein quaternary structure (1). These results suggest that the slower reaction with NADH of AIF-G307E in comparison to the wild-type protein might be at the basis of the pathogenic mechanism of the mutation. Furthermore, in the light of the proposed role of AIF as a switch in sensing the mitochondrial redox state and/or NAD(H) concentration (1), our data underscore the importance of a ready reactivity of AIF toward NADH for the full functional integrity of the mitochondrion. This work has been supported by a PRIN2008 grant awarded by the Italian Ministry of Education and University (MIUR) to M.A. Vanoni. 1. Sevrioukova IF. Antioxid Redox Signal. 2011; 14: 2545-79. 2. Ghezzi D, et al. Am J Hum Genet. 2010; 86: 639-49. 3. Berger I, et al. Mol Genet Metab. 2011; 104: 517-20.