Protein: Apoptosis-inducing factor 1, mitochondrial (EC 1.6.99.-) (Programmed cell death protein 8) (O95831)
Organism: Homo sapiens (Human)
Function: Functions both as NADH oxidoreductase and as regulator of apoptosis. In response to apoptotic stimuli, it is released from the mitochondrion intermembrane space into the cytosol and to the nucleus, where it functions as a proapoptotic factor in a caspase-independent pathway. Release into the cytoplasm is mediated upon binding to poly-ADP-ribose chains (By similarity). The soluble form (AIFsol) found in the nucleus induces 'parthanatos' i.e. caspase-independent fragmentation of chromosomal DNA. Binds to DNA in a sequence-independent manner. Interacts with EIF3G, and thereby inhibits the EIF3 machinery and protein synthesis, and activates caspase-7 to amplify apoptosis. Plays a critical role in caspase-independent, pyknotic cell death in hydrogen peroxide-exposed cells. In contrast, participates in normal mitochondrial metabolism. Plays an important role in the regulation of respiratory chain biogenesis by interacting with CHCHD4 and controlling CHCHD4 mitochondrial import.
Subcellular location: Mitochondrion intermembrane space {ECO:0000269|PubMed:15775970, ECO:0000269|PubMed:24914854, ECO:0000269|PubMed:26004228}. Mitochondrion inner membrane. Cytoplasm {ECO:0000269|PubMed:15775970, ECO:0000269|PubMed:33168626}. Nucleus {ECO:0000269|PubMed:15775970, ECO:0000269|PubMed:17094969, ECO:0000269|PubMed:33168626}. Cytoplasm, perinuclear region {ECO:0000269|PubMed:17094969}. Note=Proteolytic cleavage during or just after translocation into the mitochondrial intermembrane space (IMS) results in the formation of an inner-membrane-anchored mature form (AIFmit). During apoptosis, further proteolytic processing leads to a mature form, which is confined to the mitochondrial IMS in a soluble form (AIFsol). AIFsol is released to the cytoplasm in response to specific death signals, and translocated to the nucleus, where it induces nuclear apoptosis (PubMed:15775970). Release into the cytoplasm is mediated upon binding to poly-ADP-ribose chains (By similarity). Translocation into the nucleus is promoted by interaction with (auto-poly-ADP-ribosylated) processed form of PARP1 (PubMed:33168626). Colocalizes with EIF3G in the nucleus and perinuclear region (PubMed:17094969). {ECO:0000250|UniProtKB:Q9Z0X1, ECO:0000269|PubMed:15775970, ECO:0000269|PubMed:17094969, ECO:0000269|PubMed:33168626}.; SUBCELLULAR LOCATION: [Isoform 3]: Mitochondrion intermembrane space {ECO:0000269|PubMed:20111043}. Mitochondrion inner membrane {ECO:0000269|PubMed:20111043}. Note=Has a stronger membrane anchorage than isoform 1. {ECO:0000269|PubMed:20111043}.; SUBCELLULAR LOCATION: [Isoform 4]: Mitochondrion {ECO:0000269|PubMed:16644725}. Cytoplasm, cytosol {ECO:0000269|PubMed:16644725}. Note=In pro-apoptotic conditions, is released from mitochondria to cytosol in a calpain/cathepsin-dependent manner. {ECO:0000269|PubMed:16644725}.; SUBCELLULAR LOCATION: [Isoform 5]: Cytoplasm {ECO:0000269|PubMed:16365034}.
Interaction partners:
- Endonuclease G, mitochondrial
- Peptidyl-prolyl cis-trans isomerase A
- Apoptosis regulator BAX
- Poly
- Elongation factor Tu, mitochondrial
- Mitochondrial intermembrane space import and assembly protein 40
- Glutathione reductase, mitochondrial
- Histone H2AX
- NADH dehydrogenase iron-sulfur protein 5
- Small ribosomal subunit protein bS16m
Sequence:
MFRCGGLAAGALKQKLVPLVRTVCVRSPRQRNRLPGNLFQRWHVPLELQMTRQMASSGASGGKIDNSVLVLIVGLSTVGAGAYAYKTMKEDEKRYNERISGLGLTPEQKQKKAALSASEGEEVPQDKAPSHVPFLLIGGGTAAFAAARSIRARDPGARVLIVSEDPELPYMRPPLSKELWFSDDPNVTKTLRFKQWNGKERSIYFQPPSFYVSAQDLPHIENGGVAVLTGKKVVQLDVRDNMVKLNDGSQITYEKCLIATGGTPRSLSAIDRAGAEVKSRTTLFRKIGDFRSLEKISREVKSITIIGGGFLGSELACALGRKARALGTEVIQLFPEKGNMGKILPEYLSNWTMEKVRREGVKVMPNAIVQSVGVSSGKLLIKLKDGRKVETDHIVAAVGLEPNVELAKTGGLEIDSDFGGFRVNAELQARSNIWVAGDAACFYDIKLGRRRVEHHDHAVVSGRLAGENMTGAAKPYWHQSMFWSDLGPDVGYEAIGLVDSSLPTVGVFAKATAQDNPKSATEQSGTGIRSESETESEASEITIPPSTPAVPQAPVQGEDYGKGVIFYLRDKVVVGIVLWNIFNRMPIARKIIKDGEQHEDLNEVAKLFNIHED