AIFM1

Description

The AIFM1 (apoptosis inducing factor mitochondria associated 1) is a protein-coding gene located on chromosome X.

AIFM1, also known as Apoptosis-inducing factor 1, mitochondrial, is a protein encoded by the AIFM1 gene on the X chromosome. It is located in both the mitochondria and the nucleus. AIFM1 plays a critical role in nuclear fragmentation during caspase-independent apoptosis. AIFM1 is expressed as a 613-residue precursor protein with a mitochondrial targeting sequence (MTS) and two nuclear localization sequences (NLS). The mature protein, formed after the removal of the N-terminal 54 residues, inserts into the inner mitochondrial membrane. AIFM1 folds into three domains: the FAD-binding domain, the NAD-binding domain, and the C-terminal domain. The C-terminal is responsible for AIFM1's proapoptotic activity, while the FAD-binding and NAD-binding domains exhibit the classical Rossmann topology, common in flavoproteins, and have NAD(P)H dependent reductase activity. Three alternative transcripts, encoding different isoforms, have been identified for this gene. Two of these isoforms result from alternative splicing, including or excluding the C-terminal and reductase domains. A pseudogene related to AIFM1 has been found on chromosome 10.

AIFM1 acts as both a NADH oxidoreductase and a regulator of apoptosis. In response to apoptotic signals, it is released from the mitochondria into the cytoplasm and nucleus. This release is triggered by binding to poly-ADP-ribose chains. In the nucleus, AIFM1 induces 'parthanatos', a caspase-independent fragmentation of DNA. It binds to DNA in a sequence-independent manner. AIFM1 interacts with EIF3G, inhibiting protein synthesis and activating caspase-7, amplifying apoptosis. Additionally, it plays a role in caspase-independent pyknotic cell death in cells exposed to hydrogen peroxide. Conversely, AIFM1 participates in normal mitochondrial metabolism by regulating respiratory chain biogenesis through interaction with CHCHD4, influencing its mitochondrial import.

AIFM1 is also known as AIF, AUNX1, CMT2D, CMTX4, COWCK, COXPD6, DFNX5, NADMR, NAMSD, PDCD8, SEMDHL.

Associated Diseases

• Spondyloepimetaphyseal dysplasia, X-linked, with mental deterioration
• Deafness, X-linked 5
• Leukoencephalopathy-spondyloepimetaphyseal dysplasia syndrome
• Combined oxidative phosphorylation deficiency 6
• X-linked Charcot-Marie-Tooth disease type 4
• Cowchock syndrome
• Severe X-linked mitochondrial encephalomyopathy