Apoptosis-Inducing Factor: Structure, Function, and Redox Regulation

Abstract

Apoptosis-inducing factor (AIF) is a flavin adenine dinucleotide-containing, NADH-dependent oxidoreductase residing in the mitochondrial intermembrane space whose specific enzymatic activity remains unknown. Upon an apoptotic insult, AIF undergoes proteolysis and translocates to the nucleus, where it triggers chromatin condensation and large-scale DNA degradation in a caspase-independent manner. Besides playing a key role in execution of caspase-independent cell death, AIF has emerged as a protein critical for cell survival. Analysis of in vivo phenotypes associated with AIF deficiency and defects, and identification of its mitochondrial, cytoplasmic, and nuclear partners revealed the complexity and multilevel regulation of AIF-mediated signal transduction and suggested an important role of AIF in the maintenance of mitochondrial morphology and energy metabolism. The redox activity of AIF is essential for optimal oxidative phosphorylation. Additionally, the protein is proposed to regulate the respiratory chain indirectly, through assembly and/or stabilization of complexes I and III. This review discusses accumulated data with respect to the AIF structure and outlines evidence that supports the prevalent mechanistic view on the apoptogenic actions of the flavoprotein, as well as the emerging concept of AIF as a redox sensor capable of linking NAD(H)-dependent metabolic pathways to apoptosis.

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis

“…Upon import into the mitochondria, the mitochondrial localization signal is removed, generating the mature 62-kDa protein, which is N-terminally anchored to the inner mitochondrial membrane (49). The mature form comprises a flavin adenine dinucleotide-binding domain and an NADH-binding domain, which are thought to confer electron transfer activity (12), as well as a COOH-terminal domain (50). A truncated isoform of the protein (57 kDa) is also generated in the intermembrane space after proteolytic processing, which is thought to be mediated by m-calpain, a cysteine protease (50).…”

“…The mature form comprises a flavin adenine dinucleotide-binding domain and an NADH-binding domain, which are thought to confer electron transfer activity (12), as well as a COOH-terminal domain (50). A truncated isoform of the protein (57 kDa) is also generated in the intermembrane space after proteolytic processing, which is thought to be mediated by m-calpain, a cysteine protease (50). This isoform also contains the flavin adenine dinucleotide-binding domain, NADHbinding domain, and a COOH-terminal domain and, as such, likely retains oxidoreductase activity.…”

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

“…The apoptosome, a multi-protein platform comprising a seven-spoke ring-shaped complex (Yuan and Akey, 2013), leads to activation of initiator caspase (usually caspase-9), which in turn activates executioner caspase-3 and initiates a caspase cascade, which eventually leads to demolition of the cell (Jin and El-Deiry, 2005). AIF and endonuclease G can both promote caspase-independent cell death through inducing chromatin condensation and cleavage of nuclear DNA (Li et al, 2001;Sevrioukova, 2011). Besides the fundamental role of AIF in the execution of caspase-independent cell death, AIF has emerged as an important protein for cell survival (Sevrioukova, 2011).…”

“…AIF and endonuclease G can both promote caspase-independent cell death through inducing chromatin condensation and cleavage of nuclear DNA (Li et al, 2001;Sevrioukova, 2011). Besides the fundamental role of AIF in the execution of caspase-independent cell death, AIF has emerged as an important protein for cell survival (Sevrioukova, 2011). Other mitochondrial proteins that released in the cytosol are Smac/DIABLO and Omi/HtrA2, which provides an additional mechanism for caspase activation.…”

Mitochondrial Uptake of Ca2+ and Other Bivalent Cations

“…Cell death in inflammation-associated necrosis was common, but regulation of cell numbers in tissues was little known, factors affecting cell proliferation were rather well known, but not the regulation of cell death. An early review discussing this is [42], and a recent one [43]. The former mentions mitochondrial Ca 2+ handling as one of the important factors, the other describes the important apoptosis-inducing factor (AIF).…”