AIFM2

The AIFM2 gene encodes the FSP1 protein encoded by this gene has significant homology to NADH oxidoreductases and the apoptosis-inducing factor PDCD8/AIF. Although it was originally proposed that this protein induce apoptosis due to its similarity with AIF, findings from James Olzmann's group at UC Berkeley . FSP1 acts both at the plasma membrane and at internal organelle membranes, such as at lipid droplets where it protects stored neutral lipids. == Structure ==

AIFM2 can be found only both in prokaryotes and eukaryotes. Sequence analysis reveals that the AIFM2 gene promoter contains a consensus transcription initiator sequence instead of a TATA box. Two deletion mutations at the N-terminal (aa 1–185 and 1–300) result in nuclear localization and failure to effect cell death, suggesting that AIFM2 must be associated with the mitochondria in order to induce apoptosis. Moreover, domain mapping experiments reveal that only the C-terminal 187 aa is required for apoptotic induction. Meanwhile, mutations in the N-terminal putative FAD- and ADP-binding domains, which are responsible for its oxidoreductase function, do not affect its apoptotic function, thus indicating that these two functions operate independently. It assembles stoichiometrically and noncovalently with 6-hydroxy-FAD. The AIFM2 gene contains a putative p53-binding element in intron 5, suggesting that its gene expression can be activated by p53. == Clinical significance ==

FSP1 is upregulated in several cancers and its upregulation correlates with poor prognosis. FSP1 is a NRF2 targeted gene and contributes to NRF2-dependent ferroptosis resistance. Loss of FSP1 in preclinical mouse models results in a reduction in tumor growth. Inhibitors of FSP1 have been identified to induce or sensitize cells to ferroptosis. icFSP1 has been shown to cause dissociation of FSP1 from the membrane and phase separation of FSP1 into droplets. More commonly used FSP1 inhibitors include FSEN1 and iFSP1, which are both direct competitive inhibitors that are selective to human FSP1. Whether FSP1 is an important therapeutic target remains to be determined. == Evolution ==

The phylogenetic studies indicates that the divergence of the AIFM1 and other AIFs occurred before the divergence of eukaryotes. == Interactions ==

AIFM2 is shown to interact with p53. AIFM2 is not inhibited by Bcl-2. AIFM2 can also bind the following coenzymes: • 6-hydroxy-FAD, • Flavin adenine dinucleotide (FAD), • NADPH/NADP+, • NADH/NAD+, and • pyridine nucleotide coenzyme. == References ==