Title:The Oxido-reductase Activity of the Apoptosis Inducing Factor: A Promising Pharmacological Tool?
VOLUME: 19 ISSUE: 14
Author(s):Patricia Ferreira, Raquel Villanueva, Lauriane Cabon, Santos A. Susin and Milagros Medina
Affiliation:Departamento de Bioquimica y Biologia Molecular y Celular. Facultad de Ciencias. Pedro Cerbuna 12. Universidad de Zaragoza. 50009-Zaragoza. Spain.
Keywords:Apoptosis inducing factor, NADH-reductase activity, programmed cell death, mitochondrial respiration, nucleus
Abstract:The apoptosis inducing factor (AIF) was first discovered as a caspase-independent apoptosis effector that promoted cell death
upon release from the mitochondria (triggered by pro-apoptotic stimuli) and relocalization into the nucleus, where it promotes chromatin
condensation and DNA fragmentation. AIF is a mammalian mitochondrial FAD-dependent flavoenzyme, ubiquitous in vertebrate cells,
and with orthologs in all eukaryotes. Beyond its role in apoptosis AIF has additional functions in mitochondria, mainly related with the
redox function of its flavin adenine dinucleotide cofactor (FAD), which despite being poorly understood are vital. Thus, defects in AIF
trigger major dysfunctions in oxidative phosphorylation, and cause severe illnesses related with neurodegeneration as a consequence of
mitochondriopathies. AIF folds in three modules: a FAD-binding, a nicotine adenine dinucleotide (NADH)-binding and a C-terminal
modules. Upon reduction of the flavin cofactor by NADH, conformational changes leading to AIF dimerization are proposed as a key
early event in the mitochondrial sensing/signaling functions of AIF. The recent interest in the design of new therapies to modulate
caspase-independent apoptosis pathways also makes AIF a potential pharmacological target to treat pathological disorders related with
AIF dependent mitochondriopathies. Therefore, the first step in this direction must be to understand the molecular basis of the AIF redox
reactions and their relationship with the apoptotic function. Here, we examine recent research towards the molecular mechanisms linked
to the AIF oxido-reduction properties.
