AIFM2
Description
The AIFM2 (apoptosis inducing factor mitochondria associated 2) is a protein-coding gene located on chromosome 10.
Apoptosis-inducing factor 2 (AIFM2), also known as ferroptosis suppressor protein 1 (FSP1), apoptosis-inducing factor-homologous mitochondrion-associated inducer of death (AMID), is a protein that in humans is encoded by the AIFM2 gene, also known as p53-responsive gene 3 (PRG3), on chromosome 10. This gene encodes a flavoprotein oxidoreductase that reduces coenzyme Q10, vitamin E, and vitamin K.
== Function == 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 and Marcus Conrad's group at the Helmholtz Institute demonstrated that the primary cellular function of FSP1 is to suppress lipid peroxidation and the induction of the regulated, non-apoptotic cell death pathway known as ferroptosis. Mechanistically, FSP1 reduces oxidized coenzyme Q10 (i.e., ubiquinone) to its reduced form (i.e., ubiquinol), which functions as an excellent lipophilic antioxidant to prevent the propagation of lipid peroxidation. FSP1 also may act through the reduction of other molecules, such as vitamin E and vitamin K.
== 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. Though AIFM2 also lacks a recognizable mitochondrial localization sequence and cannot enter the mitochondria, it is found to adhere to the outer mitochondrial membrane (OMM), where it forms a ring-like structure. 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.
AIFM2 is a NAD(P)H-dependent oxidoreductase that acts as a key inhibitor of ferroptosis. It catalyzes the reduction of coenzyme Q/ubiquinone-10 to ubiquinol-10 at the plasma membrane, which acts as a lipophilic radical-trapping antioxidant that prevents lipid oxidative damage and consequently ferroptosis. AIFM2 works in parallel to GPX4 to suppress phospholipid peroxidation and ferroptosis. This anti-ferroptotic function is independent of cellular glutathione levels. AIFM2 also acts as a potent radical-trapping antioxidant by mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle: it catalyzes NAD(P)H-dependent reduction of vitamin K (phylloquinone, menaquinone-4 and menadione) to hydroquinone forms. Hydroquinones act as potent radical-trapping antioxidants, inhibiting phospholipid peroxidation and ferroptosis. AIFM2 may play a role in mitochondrial stress signaling. Upon oxidative stress, it associates with the lipid peroxidation end product 4-hydroxy-2-nonenal (HNE) forming a lipid adduct devoid of oxidoreductase activity, which then translocates from mitochondria into the nucleus triggering DNA damage and cell death. AIFM2 is capable of DNA binding in a non-sequence specific way.
AIFM2 is also known as AMID, FSP1, PRG3.
