Redox-dependent changes in molecular properties of mitochondrial apoptosis-inducing factor

Mitochondrial apoptosis-inducing factor (AIF) is a central player in the caspase-independent cell death pathway whose normal physiological function remains unclear. Our study showed that naturally folded mouse AIF very slowly reacts with NAD(P)H (k(cat) of 0.2- 0.01 s(-1)) forming tight, dimeric, and airstable FADH(2)-NAD(P) charge-transfer complexes ineffective in electron transfer. FAD reduction is accompanied by a conformational change involving AIF-specific N-terminal and regulatory 509 - 559 peptides and the active site His(453), and it affects susceptibility of AIF to calpain and AIF-DNA interaction, the two events critical for initiating caspase-independent apoptosis. Based on our results, we propose that formation of long lived complexes with NAD(P) H and redox reorganization may be functionally important and enable AIF to act as a redox-signaling molecule linking NAD(P) H-dependent metabolic pathways to apoptosis.