Structural and biochemical bases of the pathogenicity of the Apoptosis Inducing Factor (AIF)

AIF is a mitochondrial intermembrane component that fulfills the double role of apoptotic signal in a caspase-independent manner (pro-death function) and of flavoprotein required for mitochondrial biogenesis and maintenance, involved in the formation of the respiratory chain complexes (pro-life function). Since 2010, an increasing number of mutations in AIFM1, the gene encoding AIF, have been identified as the cause of human neurodegenerative mitochondriopathies. This pathology reflects in neural disorders mainly leading to severe encephalopathies and denervation, seizures, blindness and deafness, associated with oxidative phosphorylation (OXPHOS) deficiency. Beyond to NADH-oxidation, it has been stressed the role of AIF in the import and folding of other mitochondrial proteins directed to the mitochondrial intermembrane space, mainly via its interaction with CHCHD4 (Coiled-coil-helix-coiled-coil-helix domain-containing protein 4). We aim to increase understanding of AIF molecular properties and details of its interaction with CHCHD4 and to reveal how they are altered in AIFM1 pathogenic variants, also in collaboration with cellular biochemists and biologists specialized in neurodegeneration. We expect to define a solid rationale based on the combination of expertise and techniques, implementing a virtuous cycle of structural, biochemical and cell-based experiments to give a comprehensive framework of AIF roles in mitochondria.

Members:
Federica Cossu (Principal investigator)
Eloise Mastrangelo
Mario Milani