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

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. •AIF is a mitochondrial NADH-dependent oxidoreductase.•Nuclear translocation of AIF occurs during cell death and has been associated with human disorders.•Under physiological settings, AIF participates to the biogenesis of the respiratory complexes.•AIFM1 mutations have been identified in patients with impaired mitochondrial bioenergetics.•Inherited AIFM1 mutations lead to a variety of clinical manifestations, including severe childhood-onset mitochondrial diseases.