Interaction with AK2A links AIFM1 to cellular energy metabolism

Apoptosis inducing factor 1 (AIFM1) is a flavoprotein essential for mitochondrial function and biogenesis. Its interaction with MIA40, the central component of the mitochondrial disulfide relay, accounts for some, but not all effects of AIFM1 loss. Our high-confidence AIFM1 interactome revealed novel interaction partners of AIFM1. For one of these interactors, adenylate kinase 2 (AK2), an essential enzyme maintaining cellular adenine nucleotide pools, AIFM1 binding specifically stabilized the isoform AK2A via interaction with its C-terminus. High resolution cryo-EM and biochemical analyses showed that both, MIA40 and AK2A bind AIFM1s C-terminal β-strand, enhancing NADH oxidoreductase activity by locking an active, dimer conformation and, in the case of MIA40, affecting the cofactor binding site. The AIFM1-AK2A interaction is crucial during respiratory conditions. We further identified ADP/ATP translocases and the ATP synthase as AIFM1 interactors, emphasizing its important regulatory role as a central, organizing platform in energy metabolism.