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 air-stable FADH2-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.
Churbanova
Inna Y
IY
Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, USA.
Sevrioukova
Irina F
IF
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005182:Flavin-Adenine Dinucleotide / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism*; D009249:NADP / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D017510:Protein Folding; D015398:Signal Transduction / Q000502:physiology*
D051033:Apoptosis Inducing Factor; C494830:AIFM1 protein, mouse; D005182:Flavin-Adenine Dinucleotide; C058805:1,5-dihydro-FAD; D009249:NADP; D004247:DNA; D002154:Calpain; D020169:Caspases