Apoptosis inducing factor and mitochondrial NADH dehydrogenases: redox-controlled gear boxes to switch between mitochondrial biogenesis and cell death.

ABSTRACT

The mitochondrial complex I serves as entry point for NADH into the electron transport chain. In animals, fungi and plants, additional NADH dehydrogenases carry out the same electron transfer reaction, however they do not pump protons. The apoptosis inducing factor (AIF, AIFM1 in humans) is a famous member of this group as it was the first pro-apoptotic protein identified that can induce caspase-independent cell death. Recent studies on AIFM1 and the NADH dehydrogenase Nde1 of baker's yeast revealed two independent and experimentally separable activities of this class of enzymes On the one hand, these proteins promote the functionality of mitochondrial respiration in different ways They channel electrons into the respiratory chain and, at least in animals, promote the import of Mia40 (named MIA40 or CHCHD4 in humans) and the assembly of complex I. On the other hand, they can give rise to pro-apoptotic fragments that are released from the mitochondria to trigger cell death. Here we propose that AIFM1 and Nde1 serve as conserved redox switches which measure metabolic conditions on the mitochondrial surface and translate it into a binary life/death decision. This function is conserved among eukaryotic cells and apparently used to purge metabolically compromised cells from populations.