The apoptosis-inducing factor family: Moonlighting proteins in the crosstalk between mitochondria and nuclei

In Homo sapiens, the apoptosis-inducing factor (AIF) family is represented by three different proteins, known as AIF, AMID and AIFL, that have in common the mitochondrial localisation in healthy cells, the presence of FAD- and NADH-dependent domains involved in an -albeit yet not well understood- oxidoreductase function and their capability to induce programmed cell death. AIF is the best characterised family member, while the information about AMID and AIFL is much scarcer. Nonetheless, available data support different roles as well as mechanisms of action of their particular apoptogenic and redox domains regarding both pro-apoptotic and anti-apoptotic activities. Moreover, diverse cellular functions, to date far from fully clarified, are envisaged for the transcripts corresponding to these three proteins. Here, we review the so far available knowledge on the moonlighting human AIF family from their molecular properties to their relevance in health and disease, through the evaluation of their potential cell death and redox functions in their different subcellular locations. This picture emerging from the current knowledge of the AIF family envisages its contribution to regulate signalling and transcription machineries in the crosstalk among mitochondria, the cytoplasm and the nucleus.