Apoptosis-Inducing Factor (AIF) in Physiology and Disease: The Tale of a Repented Natural Born Killer

Abstract

Apoptosis-inducing factor (AIF) is a mitochondrial oxidoreductase that contributes to cell death programmes and participates in the assembly of the respiratory chain. Importantly, AIF deficiency leads to severe mitochondrial dysfunction, causing muscle atrophy and neurodegeneration in model organisms as well as in humans. The purpose of this review is to describe functions of AIF and AIF-interacting proteins as regulators of cell death and mitochondrial bioenergetics. We describe how AIF deficiency induces pathogenic processes that alter metabolism and ultimately compromise cellular homeostasis. We report the currently known AIFM1 mutations identified in humans and discuss the variability of AIFM1-related disorders in terms of onset, organ involvement and symptoms. Finally, we summarize how the study of AIFM1-linked pathologies may help to further expand our understanding of rare inherited forms of mitochondrial diseases.

Keywords: Apoptosis-inducing factor (AIF); Cell death; Mitochondria; Mitochondrial diseases; Oxidative phosphorylation (OXPHOS).

Fig. 1

Pathophysiological functions of AIF. (A) Under physiological settings, AIF has a vital role in mitochondrial bioenergetics, since it supports the normal oxidative phosphorylation of the cell. Consequently, mitochondrial AIF has an impact on multiple catabolic and anabolic pathways, as well as on epigenetic processes that depend on mitochondrial metabolites. It remains unclear whether soluble AIF molecules are present in other subcellular compartments under physiological conditions. Upon detrimental signals, mitochondrial AIF indirectly modulates intracellular signaling pathways (e.g., PTEN/Akt), while cytosolic AIF binds molecular partners that determine its nuclear translocation. In the nucleus, AIF forms a degrading complex responsible for chromatinolysis and cell death. These molecular processes have been associated to an array of pathological conditions, including inherited diseases. (B) Schematic summaries of AIF-interacting proteins. Mitochondrial intermembrane space: AIF binding to CHCHD4/Mia40 contributes to the oxidative folding of electron transport chain subunits. Moreover, AIF physically interacts with mitochondria-localized PTEN, inhibits PTEN oxidation and indirectly influences Akt signaling pathway. Cytosol: upon release from the mitochondria, AIF interacts with several cytosolic proteins. The binding kinetics between HSP70 and CypA determines AIF nuclear translocation rate. In the cytosol and in the nucleus, TRX1 interaction prevents AIF oxidation in cells exposed to stress and undergoing apoptosis. Another recently identified AIF-binding partner is MIF. In a functional complex with AIF, the endonuclease MIF translocates to the nucleus and mediates chromatinolysis. During apoptosis, AIF interacts with the eukaryotic translational initiation factor EIF3g and, consequently, inhibits protein synthesis. Nucleus: along with CypA, AIF interacts with histone H2AX and forms a degrading complex that regulates DNA cleavage. At least in invertebrates, AIF regulates EndoG activity and promotes chromatin condensation.

Fig. 2

Disease-causing mutations in the AIF protein. (A) Schematic drawing of human AIF protein and the annotated disease-causing mutations identified in patients. Mutated amino acids are indicated with arrows and numbers. In the scheme, it is also indicated the mitochondrial localization sequence (MLS) and the calpain cleavage site (proteolytic cleavage) of the membrane-bound protein. FAD and NADH represent the FAD-binding domains and NADH-binding motif, respectively. Numbers at the bottom correspond to the first and last amino acid of each domain. (B) Table reports the identified disease-causing mutations and describes the clinical presentations in patients. Colour-code rectangles indicate AIF domains. The table includes also a group of mutations (others) that have been identified in unrelated families of individuals with X-linked progressive auditory and peripheral sensory neuropathy. References (Ref.) are the following: (a) (Ghezzi et al., 2010); (b) (Hu et al., 2017; Sancho et al., 2017); (c) (Mierzewska et al., 2017; Miyake et al., 2017); (d) (Kettwig et al., 2015); (e) (Ardissone et al., 2015); (f) (Berger et al., 2011); (g) (Diodato et al., 2016); (h) (Morton et al., 2017); (i) (Rinaldi et al., 2012); (j) (Zong et al., 2015).