Affinage

AIFM1

Apoptosis-inducing factor 1, mitochondrial · UniProt O95831

Audit flag: ungrounded claim
Length
613 aa
Mass
66.9 kDa
Annotated
2026-06-09
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AIFM1 (AIF) is a FAD-dependent NADH oxidoreductase of the mitochondrial intermembrane space that performs two genetically separable functions: support of mitochondrial respiration under normal conditions and execution of caspase-independent cell death upon apoptotic or necrotic stress (PMID:10381654, PMID:12432061, PMID:15526035). In its housekeeping role, AIF is N-terminally anchored to the inner mitochondrial membrane and acts as an integral component of the MIA40/CHCHD4 disulfide-relay import machinery: it both imports MIA40/CHCHD4 and stabilizes the relay, enabling mitochondrial import of nuclear-encoded respiratory subunits such as NDUFS5 and thereby driving complex I biogenesis and OXPHOS (PMID:20494118, PMID:26004228, PMID:35859387). Loss of AIF collapses complex I content and forces a glycolytic shift (PMID:15526035), and this respiratory function—independent of its apoptotic activity—is sufficient to drive Kras-driven lung tumor progression (PMID:31133695). The AIF–CHCHD4 interaction is gated by post-translational modification, requiring SIRT5-mediated desuccinylation and proper AIF dimerization (PMID:36653443, PMID:37365177). Crystallographic and reconstitution work shows the apoptogenic and oxidoreductase activities are dissociable, with AIF functioning in membranes as a rotenone-sensitive NADH:ubiquinone oxidoreductase (PMID:12432061, PMID:26063804). In the death program, AIF must be proteolytically released from its membrane anchor—a step executed by calpains downstream of calcium overload and BID/tBID-mediated BAX activation (PMID:15941767, PMID:20494118, PMID:21738214, PMID:33597260)—after which it translocates to the nucleus and assembles a DNA-degrading complex with cyclophilin A and γH2AX via its C-terminal proline-rich domain to drive large-scale chromatinolysis (PMID:14716299, PMID:20360685, PMID:22972376). This pathway is held in check by retention and modification factors including HSP70 and LONP1, redox modulation by thioredoxin-1, and regulatory PTMs (OTUD1 deubiquitination, PAK5 phosphorylation blocking importin-α3 binding) (PMID:15244251, PMID:26119781, PMID:33898171, PMID:33867848, PMID:34974310). Pathogenic AIFM1 variants impair redox properties, dimerization, and CHCHD4 binding, causing mitochondrial respiratory deficiency (PMID:27178839, PMID:37365177).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1999 High

    Established AIF as the founding mitochondrial effector of caspase-independent death, answering whether mitochondria harbor an apoptogenic factor distinct from cytochrome c.

    Evidence Subcellular fractionation, nuclear microinjection, and cDNA cloning identifying an IMS flavoprotein that translocates to the nucleus to drive chromatin condensation and ~50 kb DNA fragmentation

    PMID:10381654 PMID:10913597

    Open questions at the time
    • Did not identify the nuclear DNA-degrading partners
    • Mechanism of release from mitochondria unresolved
  2. 2002 High

    Demonstrated that AIF's oxidoreductase and apoptogenic activities are structurally and functionally separable, reframing AIF as a bifunctional protein rather than a single-activity death factor.

    Evidence Crystal structures of human/mouse AIF with active-site mutagenesis dissociating DNA-binding-dependent chromatin condensation from NADH oxidase activity; HSP70 neutralization by Co-IP/KO

    PMID:12022952 PMID:12432061

    Open questions at the time
    • Physiological substrate of the oxidoreductase activity not defined
    • How DNA binding triggers chromatinolysis unclear
  3. 2002 High

    Showed the death pathway is evolutionarily conserved, establishing AIF homologs as components of a mitochondria-initiated DNA degradation program acting with endonuclease G.

    Evidence RNAi, localization, Co-IP, and DNA degradation assays in C. elegans (WAH-1) defining caspase-dependent release and cooperation with CPS-6/EndoG

    PMID:12446902

    Open questions at the time
    • Conservation of the EndoG cooperation in mammals not addressed here
  4. 2003 High

    Ordered the mitochondrial apoptogenic release hierarchy, showing AIF release is downstream of and dependent on caspase activation rather than concurrent with cytochrome c.

    Evidence Isolated mitochondria assays, zVAD-fmk, and Apaf-1 KO cells distinguishing Bax/Bak-driven release of cytochrome c from caspase-dependent AIF/EndoG release

    PMID:12941691

    Open questions at the time
    • Protease(s) directly cleaving membrane-anchored AIF not identified here
  5. 2004 High

    Revealed an unexpected housekeeping role for AIF in respiratory chain complex I biogenesis, separating its survival function from its death function.

    Evidence Homologous-recombination KO, siRNA, BN-PAGE, metabolic flux, and Harlequin mouse analysis showing reduced complex I content and enhanced glycolysis on AIF loss

    PMID:15526035

    Open questions at the time
    • Molecular mechanism linking AIF to complex I assembly not yet defined
  6. 2004 High

    Identified the nuclear partners that convert AIF into an active nuclease complex, beginning to explain how AIF—lacking intrinsic nuclease activity—degrades DNA.

    Evidence Mass spectrometry, Co-IP, pull-downs, CypA-KO cells, and mutagenesis showing direct AIF-CypA interaction and synergistic DNA degradation; yeast Aif1p reconstitution and genetic epistasis with cyclophilin/YCA1

    PMID:14716299 PMID:15381687

    Open questions at the time
    • Whether CypA is the catalytic nuclease vs. a cofactor unresolved
    • Additional complex members not yet defined
  7. 2005 High

    Defined upstream release and retention controls, showing calpain directly liberates AIF from mitochondria while HSP70 sequesters it cytosolically.

    Evidence Cell-free mitochondrial release with purified calpain I, BimEL siRNA, calpain inhibitors; HSP70 Co-IP and transgenic hypoxia-ischemia mouse model

    PMID:15244251 PMID:15941767

    Open questions at the time
    • Exact AIF cleavage site by calpain not mapped here
    • HSP70 study single lab
  8. 2006 Medium

    Placed AIF under transcriptional control of p53, linking the DNA-damage response to AIF abundance and caspase-independent death.

    Evidence ChIP, luciferase reporter, and p53-deficient cells with large-scale DNA fragmentation readout

    PMID:16729031

    Open questions at the time
    • Single lab
    • Contribution relative to post-translational regulation unclear
  9. 2008 High

    Positioned AIF as the obligatory executioner downstream of lipid peroxidation in a GPx4-controlled cell death pathway.

    Evidence Inducible GPx4 KO in mice/cells, AIF siRNA, 12/15-lipoxygenase inhibitors, and alpha-tocopherol rescue establishing AIF's epistatic position

    PMID:18762024

    Open questions at the time
    • How lipid peroxidation signals to AIF release not mechanistically defined
  10. 2009 Medium

    Identified PAR polymer as the nucleus-to-mitochondria signal initiating AIF release in PARP-1-dependent parthanatos.

    Evidence Review compiling PAR localization, AIF release assays, and PARP-1 genetic/pharmacological manipulation

    PMID:19332058

    Open questions at the time
    • Review-level synthesis
    • Direct PAR-AIF binding mechanism not established here
  11. 2010 High

    Resolved the molecular architecture of the lethal nuclear complex, mapping AIF's C-terminal proline-rich domain as the H2AX-binding interface required for chromatinolysis.

    Evidence Co-IP, directed mutagenesis of AIF PBD (residues 543-559), H2AX-KO cells, CypA siRNA, and MNNG necrosis assays; membrane-anchorage fractionation defining the cleavage requirement

    PMID:20360685 PMID:20494118

    Open questions at the time
    • Stoichiometry and catalytic mechanism of the AIF/H2AX/CypA complex unresolved
  12. 2011 High

    Wired the proximal necroptotic cascade upstream of AIF, showing calpain-processed tBID activates BAX to permit AIF release.

    Evidence KO MEFs with BID rescue, calpain cleavage assays, and BID point mutants (G70A, Δ68-71) in MNNG necroptosis

    PMID:21738214

    Open questions at the time
    • Direct biochemical link between BAX activation and calpain-mediated AIF cleavage not fully reconstituted
  13. 2011 Medium

    Proposed a non-canonical ER/MAM-vesicular route for AIF mitochondrial import requiring fission and tethering machinery.

    Evidence Sucrose-gradient fractionation and DRP1/ATAD3A/Mfn-2 siRNA knockdowns

    PMID:22134679

    Open questions at the time
    • Single lab with limited orthogonal validation
    • Reconciliation with canonical IMS import not addressed
  14. 2012 High

    Established the upstream kinase signal licensing chromatinolysis, showing ATM/DNA-PK-generated γH2AX is required for AIF-mediated DNA degradation.

    Evidence ATM/DNA-PK inhibitors, H2AX-KO cells, S139A loss-of-function and S139E phosphomimetic rescue in MNNG necroptosis

    PMID:22972376

    Open questions at the time
    • How γH2AX promotes AIF complex assembly mechanistically unclear
  15. 2015 High

    Defined the mechanism of AIF's respiratory function, showing AIF imports and stabilizes CHCHD4/MIA40 to power the IMS disulfide relay.

    Evidence Co-IP, siRNA, CHCHD4 mitochondrial-targeting rescue, respiratory assays, and AIF-KO embryoid bodies; membrane-reconstituted NDH-2 activity and E. coli complementation

    PMID:26004228 PMID:26063804

    Open questions at the time
    • Full set of relay substrates not enumerated here
    • Relationship between NDH-2 quinone activity and import role unclear
  16. 2015 Medium

    Uncovered redox and signaling roles beyond respiration, including AIF-mediated protection of PTEN from oxidation and Trx1 restraint of nuclear AIF.

    Evidence Co-IP, lipid phosphatase and oxidation assays, xenografts (PTEN); Trx1 active-site mutants, fractionation, and DNA damage assays

    PMID:26119781 PMID:26415504

    Open questions at the time
    • Both single-lab
    • Direct redox chemistry between AIF and partners not fully defined
  17. 2016 High

    Linked AIFM1 missense variants to mitochondrial disease through distinct molecular defects in redox properties or protein stability.

    Evidence Purification, spectroscopy, redox and respiration assays, and structural analysis of V243L, G262S, G308E, G338E variants

    PMID:27178839

    Open questions at the time
    • Genotype-phenotype correlation imperfect (G262S more severe biochemically than clinically)
  18. 2016 Medium

    Added RIP3 as a nuclear AIF partner in ischemic programmed necrosis.

    Evidence Co-IP, co-localization, necrostatin-1 inhibition, and nuclear fractionation in a rat cerebral ischemia model

    PMID:27377128

    Open questions at the time
    • Single lab
    • Functional consequence of RIP3-AIF binding for DNA degradation not mechanistically dissected
  19. 2017 High

    Mapped the AIF-CypA interface at atomic resolution and showed it overlaps the cyclosporin A site, enabling pharmacological targeting.

    Evidence NMR spectroscopy, pull-downs, modeling, and CsA competition binding of AIF peptides

    PMID:28442737

    Open questions at the time
    • Whether competing the interface blocks chromatinolysis in vivo not tested here
  20. 2019 High

    Demonstrated that AIF's mitochondrial respiratory function, not its apoptotic activity, drives tumor progression in vivo.

    Evidence Conditional AIF KO in KrasG12D mouse lung cancer with WT vs. apoptosis-mutant AIF re-expression and Seahorse profiling

    PMID:31133695

    Open questions at the time
    • Therapeutic exploitability of AIF respiratory dependence untested here
  21. 2021 High

    Defined a coherent calcium → calpain → AIF cleavage → nuclear translocation axis in cardiomyocyte necrosis, integrating redox potentiation and CypA-dependent import.

    Evidence Calpain-1 inhibition, CAST overexpression, AIF-mimetic peptide, and arrhythmogenic cardiomyopathy mouse/cardiomyocyte models

    PMID:33597260

    Open questions at the time
    • Precise calpain cleavage site and thioredoxin-2 redox target residues not fully mapped
  22. 2021 Medium

    Established PTM control of AIF's dual functions and identified retention factors, with OTUD1 and PAK5 acting at distinct steps and LONP1 restraining nuclear translocation.

    Evidence Site-specific K244/K255 deubiquitination assays (OTUD1); Thr281 phosphorylation and importin-α3 Co-IP (PAK5); LONP1 Co-IP/MS and conditional KO oocyte model

    PMID:33867848 PMID:33898171 PMID:34974310

    Open questions at the time
    • All single-lab
    • Crosstalk and hierarchy among these PTMs unresolved
  23. 2022 High

    Consolidated the AIFM1–MIA40 relay mechanism, showing AIFM1 loss leaves MIA40 monomeric and stalls complex I via failed NDUFS5 import and its cytosolic degradation.

    Evidence In vitro complex reconstitution, AIFM1-KO HEK293 cells, MIA40 substrate import assays, NDUFS5 localization, and BN-PAGE; UBA52-AIF ubiquitination linked to hypoxic mitochondrial dysfunction

    PMID:35090552 PMID:35859387

    Open questions at the time
    • Breadth of relay substrates beyond NDUFS5 incompletely defined
    • UBA52 study single lab
  24. 2023 High

    Identified desuccinylation as a prerequisite for the AIF-CHCHD4 interaction and showed how a pathogenic dimerization defect converts AIF from respiratory support to a death trigger.

    Evidence SIRT5 IP-MS/Co-IP/KO with succinylation and ETC import assays; patient iPSC neurons with CRISPR isogenic correction showing impaired dimerization, calcium overload, and calpain-driven AIF nuclear translocation

    PMID:36653443 PMID:37365177

    Open questions at the time
    • SIRT5 study single lab
    • Generality of the dimerization-to-death mechanism across variants untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory layers (transcriptional, redox, succinylation, ubiquitination, phosphorylation, and protein retention) are integrated to set the threshold between AIF's respiratory and lethal functions remains unresolved.
  • No unified model reconciling PTM crosstalk
  • Catalytic basis of nuclear DNA degradation by the AIF/CypA/H2AX complex undefined
  • Physiological electron acceptor of mitochondrial AIF oxidoreductase not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0003677 DNA binding 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 4 GO:0005739 mitochondrion 4 GO:0005829 cytosol 2
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-1430728 Metabolism 2 R-HSA-392499 Metabolism of proteins 2
Partners
CHCHD4CYPA (PPIA)H2AXHSP70LONP1PTENRIPK3TXN
Complex memberships
AIF-CypA-H2AX nuclear DNA-degrading complexAIFM1-CHCHD4/MIA40 disulfide relay

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 AIF is a mitochondrial intermembrane space flavoprotein that, upon apoptosis induction, translocates from mitochondria to the nucleus where it induces caspase-independent chromatin condensation and large-scale (~50 kb) DNA fragmentation. The protein contains an oxidoreductase domain with conserved FAD and NAD binding residues. Subcellular fractionation, nuclear microinjection, cDNA cloning, domain analysis Cell death and differentiation High 10381654
2000 AIF is a ubiquitously expressed X-linked gene product imported into the mitochondrial intermembrane space as a FAD-containing flavoprotein; upon apoptotic stimuli it translocates through the outer mitochondrial membrane to the cytosol and nucleus, inducing chromatin condensation and ~50 kb DNA fragmentation in a caspase-independent manner. Subcellular fractionation, immunofluorescence, microinjection into purified nuclei, Western blot FEBS letters High 10913597
2002 AIF exhibits NADH oxidase activity and can participate in regulation of apoptotic mitochondrial membrane permeabilization in addition to its nuclear apoptogenic function. HSP70 neutralizes AIF in a reaction independent of ATP and the HSP70 ATP-binding domain, inhibiting caspase-independent cell death. Co-immunoprecipitation, microinjection of anti-AIF antibody, AIF gene knockout, HSP70 overexpression Biochimie Medium 12022952
2002 Crystal structures of human and mouse AIF were determined; mutations that abolish the AIF-DNA electrostatic interaction suppress AIF-induced chromatin condensation but have no effect on NADH oxidase activity, demonstrating that the apoptogenic and oxidoreductase functions of AIF are dissociable. Crystal structure determination, active-site mutagenesis, nuclear condensation assay Journal of cell science High 12432061
2002 In C. elegans, the AIF homolog WAH-1 localizes to mitochondria and is released into the cytosol and nucleus in a CED-3 (caspase)-dependent manner downstream of the BH3-domain protein EGL-1. WAH-1 associates and cooperates with CPS-6/endonuclease G to promote apoptotic DNA degradation, defining a conserved mitochondria-initiated DNA degradation pathway. RNAi knockdown, subcellular localization, co-immunoprecipitation, DNA degradation assay Science High 12446902
2003 Pro-apoptotic Bcl-2 proteins (Bax/Bak) cause release of cytochrome c, Smac/DIABLO, and HtrA2/Omi but NOT AIF or EndoG from mitochondria; release of AIF and EndoG requires caspase activation downstream of Bax/Bak permeabilization, demonstrating a hierarchical ordering of mitochondrial apoptogenic factor release. Isolated mitochondria assay, caspase inhibitor (zVAD-fmk), Apaf-1 knockout cells, Western blot of subcellular fractions The EMBO journal High 12941691
2004 Human and mouse cells lacking AIF via homologous recombination or siRNA show high lactate production, enhanced glycolysis, and severe reduction of respiratory chain complex I activity. AIF-deficient cells have reduced complex I content and subunit levels, pointing to a role of AIF in biogenesis/maintenance of complex I. Harlequin mice with reduced AIF also show reduced OXPHOS in retina and brain with reduced complex I subunits. Homologous recombination KO, siRNA, metabolic flux measurements, BN-PAGE, Western blot of complex I subunits The EMBO journal High 15526035
2004 Cyclophilin A (CypA) directly interacts with AIF as determined by mass spectrometry, co-immunoprecipitation, and pull-down assays. AIF and CypA co-localize in the nucleus during early caspase-independent chromatin condensation and synergize in vitro to degrade plasmid DNA and induce DNA loss in purified nuclei. AIF mutants lacking the CypA-binding domain are inefficient apoptosis sensitizers. Mass spectrometry, co-immunoprecipitation, pull-down assay, in vitro DNA degradation, CypA knockout cells, mutagenesis Oncogene High 14716299
2004 The yeast AIF homolog Ynr074cp (renamed Aif1p) localizes to mitochondria and translocates to the nucleus in response to apoptotic stimuli. Purified Ynr074cp degrades yeast nuclei and plasmid DNA. YNR074C disruption rescues yeast from oxygen stress and delays age-induced apoptosis; its pro-death effect is attenuated by disruption of cyclophilin A or the yeast caspase YCA1. Gene disruption, overexpression, subcellular localization, in vitro DNA degradation assay, genetic epistasis The Journal of cell biology High 15381687
2005 Hsp70 binds directly to AIF (shown by co-immunoprecipitation) and sequesters it in the cytosol, preventing nuclear translocation of AIF and reducing neonatal hypoxic/ischemic brain injury. Hsp70 overexpression reduced nuclear AIF without affecting cytosolic AIF levels. Co-immunoprecipitation, Western blot of subcellular fractions, transgenic mouse model of hypoxia-ischemia Journal of cerebral blood flow and metabolism Medium 15244251
2005 BimEL upregulation by MPP+ leads to increased calpain I activity, which directly mediates AIF release from isolated mitochondria. Calpain inhibition or BimEL knockdown reduces AIF release and cell death. Under cell-free conditions, activated purified calpain I releases AIF from isolated mitochondria independently of BimEL or JNK. Cell-free mitochondrial release assay with purified calpain I, siRNA knockdown of BimEL, calpain inhibitors, Western blot FASEB journal High 15941767
2006 AIF gene expression is positively regulated by p53 at basal levels via a p53 responsive element in the AIF gene promoter that is bound by p53 within cells. p53-driven large-scale DNA fragmentation (an AIF activity hallmark) is compromised in cells lacking functional p53. Caspase-independent death is also impaired in p53-deficient cells. Chromatin immunoprecipitation, luciferase reporter assay, p53-deficient cells, large-scale DNA fragmentation assay Cell death and differentiation Medium 16729031
2008 GPx4 inactivation triggers 12/15-lipoxygenase-derived lipid peroxidation as a specific downstream event that triggers AIF-mediated cell death. siRNA-mediated AIF silencing entirely prevents cell death in this pathway. Neuron-specific GPx4 depletion causes neurodegeneration via this pathway. Inducible GPx4 knockout in mice and cells, siRNA silencing of AIF, 12/15-lipoxygenase inhibitors, alpha-tocopherol rescue Cell metabolism High 18762024
2009 Poly(ADP-ribose) (PAR) polymer generated in the nucleus by PARP-1 after DNA damage translocates to mitochondria to mediate AIF release; this PAR signal is the key event initiating nuclear-to-mitochondrial crosstalk in parthanatos (PARP-1-dependent caspase-independent cell death). Review summarizing experimental evidence including PAR polymer localization, AIF release assays, and PARP-1 genetic/pharmacological manipulation Experimental neurology Medium 19332058
2010 AIF associates with histone H2AX in the nucleus through its C-terminal proline-rich binding domain (PBD, residues 543–559), generating an active DNA-degrading complex with cyclophilin A (CypA). Deletion or mutagenesis of the AIF C-terminal PBD abolishes AIF/H2AX interaction and AIF-mediated chromatinolysis. H2AX genetic ablation or CypA downregulation confers resistance to programmed necrosis. Co-immunoprecipitation, directed mutagenesis, H2AX knockout cells, siRNA knockdown of CypA, MNNG-induced necrosis assay The EMBO journal High 20360685
2010 AIF is N-terminally anchored to the inner mitochondrial membrane rather than being freely soluble in the intermembrane space; it must be proteolytically cleaved from its membrane anchor prior to release into the cytosol. Membrane fractionation, protease protection assay, reviewed experimental evidence Biochemical and biophysical research communications Medium 20494118
2011 In MNNG-induced necroptosis, BID acts as a link between calpain activation and BAX activation upstream of AIF release. Calpains directly process BID into tBID; calpain non-cleavable BID mutants (BID-G70A or BID-Δ68-71) abolish BAX activation and necroptosis. BID genetic ablation blocks both BAX activation and AIF-mediated necroptosis. Knockout MEFs, BID reintroduction rescue, calpain cleavage assay, BID point mutants, Western blot, cell death assays Cell death and differentiation High 21738214
2011 AIF is imported into mitochondria via the endoplasmic reticulum through mitochondria-associated membranes (MAM) and transport vesicles. DRP1, ATAD3A, and mitofusin-2 are required for this import pathway; knockdown of DRP1 increased AIF in MAM while reducing it in mitochondria; knockdown of ATAD3A or Mfn-2 increased cytosolic AIF transport vesicles. Sucrose gradient ultracentrifugation, immunoblotting, DRP1/ATAD3A/Mfn-2 siRNA knockdown International journal of molecular medicine Medium 22134679
2012 ATM and DNA-PK kinases phosphorylate histone H2AX at Ser139 (generating γH2AX) in a synergistic manner during MNNG-induced necroptosis. γH2AX is required for AIF-mediated chromatinolysis; H2AX S139A mutation or H2AX knockout abolishes both chromatinolysis and necroptosis, whereas phosphomimetic H2AX-S139E restores sensitivity. ATM/DNA-PK pharmacological inhibitors, H2AX knockout cells, H2AX point mutant rescue, siRNA Cell death & disease High 22972376
2015 AIF directly interacts with CHCHD4 (human MIA40), the central component of the mitochondrial intermembrane space import machinery. AIF depletion or hypomorphic mutation reduces CHCHD4 protein levels by diminishing its mitochondrial import. CHCHD4 depletion alone recapitulates the respiratory defect of AIF-deficient cells. Restoring CHCHD4 mitochondrial localization independently of AIF rescues respiratory function and enables cavitation in AIF-deficient embryoid bodies. Co-immunoprecipitation, siRNA, CHCHD4 mitochondrial targeting construct rescue, respiratory chain activity assay, AIF-KO embryoid bodies Molecular cell High 26004228
2015 AIF physically interacts with and protects PTEN from oxidation-mediated inactivation. AIF knockdown causes oxidative inactivation of PTEN's lipid phosphatase activity, leading to Akt activation, GSK-3β phosphorylation, β-catenin activation, and ultimately EMT and tumor metastasis. PTEN was also identified as a mitochondrial protein. Co-immunoprecipitation, lipid phosphatase activity assay, AIF knockdown, oxidation assay, xenograft model EMBO reports Medium 26415504
2015 Reconstituted AIF and AMID, when inserted into bacterial or mitochondrial membranes, function as NADH:ubiquinone oxidoreductases (NDH-2) sensitive to rotenone and the quinone-binding inhibitor HQNO, and support NADH-linked proton pumping. N-terminally tagged AIF enhances growth of E. coli lacking complex I and NDH-2; NADH-binding site mutants and disease mutant AIFΔR201 show decreased activity. Membrane reconstitution, NADH:ubiquinone oxidoreductase activity assay, proton pumping assay, E. coli growth complementation, mutagenesis The Journal of biological chemistry High 26063804
2015 Cytosolic/nuclear thioredoxin-1 (Trx1) directly interacts with AIF under physiological conditions via its active-site cysteines; this interaction is disrupted by oxidative stress. Nuclear Trx1 hinders AIF-DNA interaction, attenuating AIF-mediated DNA damage. Disruption of the Trx1-AIF interaction correlates with nuclear AIF translocation. Co-immunoprecipitation, Trx1 active-site mutants, oxidative stress perturbation, nuclear fractionation, DNA damage assay Free radical biology & medicine Medium 26119781
2016 Structural and functional characterization of four pathological AIFM1 variants (V243L, G262S, G308E, G338E): G308E drastically impairs redox properties and mitochondrial respiration; V243L and G338E show minimal structural changes, suggesting reduced cellular expression is the pathogenic driver; G262S shows structural/redox alterations more severe than predicted by clinical phenotype. Protein purification, spectroscopic characterization, redox activity assay, cell respiration measurement, structural analysis Journal of molecular biology High 27178839
2017 The AIF(370–394) peptide binds CypA at a surface overlapping with the cyclosporin A binding site near the catalytic pocket; NMR and biochemical mapping established that AIF(Δ1–121) and the AIF(370–394) peptide bind the same CypA surface and compete with CsA. NMR spectroscopy, pull-down assay, molecular modeling, competition binding assay Scientific reports High 28442737
2017 High-risk HPV E6 oncoprotein (HPV16 E6) directly binds all three forms of AIF and induces proteasome-dependent reduction of AIF expression, thereby suppressing AIF-mediated caspase-independent apoptosis. Low-risk HPV6 E6 also binds AIF but does not reduce its levels. Co-immunoprecipitation, MG132 proteasome inhibitor, flow cytometry for chromatin degradation, AIF knockdown Scientific reports Medium 32848167
2019 Deletion of AIF in a KrasG12D-driven mouse lung cancer model causes OXPHOS deficiency and metabolic shift toward glycolysis, reducing tumor growth. Re-expression of wild-type or apoptosis-deficient AIF (intact mitochondrial function) both restored OXPHOS and reduced animal survival, demonstrating that AIF's mitochondrial respiratory function (not its apoptotic function) drives lung cancer progression. Conditional AIF KO mouse in KrasG12D model, re-expression of WT vs. apoptosis-mutant AIF, Seahorse metabolic profiling Cell research High 31133695
2021 CAPN1 (calpain-1) is activated by calcium overload, associates with mitochondria, and cleaves mitochondrion-bound AIF; cleaved AIF translocates to the nucleus to trigger large-scale DNA fragmentation and necrotic cell death in cardiomyocytes. AIF oxidation at cysteine residues by a depleted thioredoxin-2 system potentiates this effect. A cyclophilin A (PPIA)-binding AIF peptide blocks PPIA-mediated AIF nuclear translocation. Calpain-1 inhibitor, CAST overexpression, AIF-mimetic peptide, mouse model of arrhythmogenic cardiomyopathy, ES cell-derived cardiomyocytes, immunoprecipitation Science translational medicine High 33597260
2021 OTUD1 deubiquitinase deubiquitinates AIF at K244, disrupting mitochondrial structure and compromising OXPHOS, and at K255, enhancing AIF DNA-binding ability to promote parthanatos. OTUD1 thus controls both the mitochondrial survival and nuclear apoptogenic functions of AIF through distinct ubiquitination sites. Deubiquitination assay, specific ubiquitination site mutagenesis (K244, K255), OXPHOS measurement, DNA-binding assay, cell death assay Advanced science Medium 33898171
2021 PAK5 phosphorylates AIF at Thr281, inhibiting formation of the AIF/importin α3 complex and thereby preventing AIF nuclear translocation. PAK5 also decreases mitochondrial membrane permeability to reduce AIF release from mitochondria. Phosphorylation assay, AIF Thr281 mutagenesis, co-immunoprecipitation with importin α3, mitochondrial membrane permeability measurement, in vivo breast cancer model International journal of biological sciences Medium 33867848
2022 AIFM1 forms a stable long-lived complex with MIA40/CHCHD4 in vitro and in cells/tissues. In AIFM1-KO HEK293 cells, MIA40 is present in monomeric form and cannot efficiently interact with or import specific substrates, particularly NDUFS5. Loss of mitochondrial NDUFS5 causes its cytosolic proteasomal degradation and stalls complex I assembly. AIFM1 thus serves dual overlapping functions: importing MIA40 and constituting an integral part of the disulfide relay. In vitro complex reconstitution, AIFM1 KO cell lines, MIA40 substrate import assay, NDUFS5 localization, complex I assembly analysis, BN-PAGE The EMBO journal High 35859387
2023 SIRT5-mediated desuccinylation of AIFM1 is required for the AIFM1-CHCHD4 interaction; reduced SIRT5 increases AIFM1 succinylation, abolishing the AIFM1-CHCHD4 interaction and reducing ETC complex subunit import, leading to mitochondrial dysfunction. IP-MS and Co-IP confirmed AIFM1 as a direct SIRT5 substrate. Immunoprecipitation-mass spectrometry (IP-MS), co-immunoprecipitation, SIRT5 overexpression/KO, succinylation assay, ETC complex subunit measurement Experimental & molecular medicine Medium 36653443
2023 An AIFM1 variant (c.1265 G>A) causes a splicing change resulting in impaired AIF dimerization, which weakens AIF-CHCHD4 interaction, inhibits mitochondrial import of ETC complex subunits, impairs MICU1-MICU2 heterodimerization leading to mitochondrial calcium overload, and activates calpain-mediated AIF cleavage and nuclear translocation triggering caspase-independent apoptosis in patient iPSC-derived neurons. Patient iPSC-derived neurons, CRISPR/Cas9 isogenic correction, Co-IP for AIF-CHCHD4 interaction, ETC subunit import assay, mitochondrial Ca2+ measurement, calpain activity assay Cell death & disease High 37365177
2021 LONP1 directly interacts with AIFM1 in mitochondria; LONP1 ablation leads to AIFM1 translocation from cytoplasm to nucleus causing oocyte apoptosis and progressive oocyte death. Co-immunoprecipitation/LC-MS, conditional Lonp1 knockout mice, AIFM1 nuclear translocation by immunofluorescence EBioMedicine Medium 34974310
2016 RIP3 forms a complex with AIF in the nucleus following ischemia/reperfusion injury; their interaction was detected by co-immunoprecipitation and co-localization, and formation of this RIP3-AIF nuclear complex is critical for ischemic neuronal DNA degradation and programmed necrosis. The necrostatin-1 RIP3 inhibitor prevents both complex formation and nuclear translocation. Immunoprecipitation, immunofluorescence co-localization, necrostatin-1 inhibitor, Western blot of nuclear fractions, rat global cerebral ischemia model Scientific reports Medium 27377128
2022 AIF ubiquitination by interaction with UBA52 under hypoxia leads to mitochondrial dysfunction (impaired OXPHOS, increased glycolysis and ROS) via loss of complex I activity. AIF deficiency also triggers abnormal mitophagy through AIF-UBA52 interaction. AAV-mediated AIF overexpression protects against hypoxia-induced pulmonary vascular remodeling. Co-IP with mass spectrometry, Seahorse extracellular flux analysis, AAV overexpression, electron microscopy Cell & bioscience Medium 35090552

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell metabolism 1207 18762024
2004 AIF deficiency compromises oxidative phosphorylation. The EMBO journal 517 15526035
2004 Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene 451 15077142
2002 Apoptosis-inducing factor (AIF): a novel caspase-independent death effector released from mitochondria. Biochimie 412 12022952
2004 Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends in pharmacological sciences 398 15120492
2002 Apoptosis-inducing factor (AIF): key to the conserved caspase-independent pathways of cell death? Journal of cell science 397 12432061
1999 Apoptosis inducing factor (AIF): a phylogenetically old, caspase-independent effector of cell death. Cell death and differentiation 395 10381654
2000 Apoptosis-inducing factor (AIF): a ubiquitous mitochondrial oxidoreductase involved in apoptosis. FEBS letters 373 10913597
2003 Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak-mediated permeabilization. The EMBO journal 366 12941691
2009 Poly(ADP-ribose) signals to mitochondrial AIF: a key event in parthanatos. Experimental neurology 336 19332058
2002 Mechanisms of AIF-mediated apoptotic DNA degradation in Caenorhabditis elegans. Science (New York, N.Y.) 333 12446902
2004 An AIF orthologue regulates apoptosis in yeast. The Journal of cell biology 331 15381687
2004 AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis. Oncogene 225 14716299
2010 Mitochondrial regulation of cell death: processing of apoptosis-inducing factor (AIF). Biochemical and biophysical research communications 208 20494118
2010 AIF promotes chromatinolysis and caspase-independent programmed necrosis by interacting with histone H2AX. The EMBO journal 187 20360685
2015 Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis. Molecular cell 169 26004228
2018 Apoptosis-Inducing Factor (AIF) in Physiology and Disease: The Tale of a Repented Natural Born Killer. EBioMedicine 167 29605508
2006 Regulation of AIF expression by p53. Cell death and differentiation 164 16729031
2005 Hsp70 overexpression sequesters AIF and reduces neonatal hypoxic/ischemic brain injury. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 159 15744251
2009 AIF: not just an apoptosis-inducing factor. Annals of the New York Academy of Sciences 150 19723031
2002 Dueling activities of AIF in cell death versus survival: DNA binding and redox activity. Cell 149 12408857
2011 AIF-mediated caspase-independent necroptosis: a new chance for targeted therapeutics. IUBMB life 145 21438113
2007 AIF-mediated programmed necrosis: a highly regulated way to die. Cell cycle (Georgetown, Tex.) 133 17912035
2010 Life with or without AIF. Trends in biochemical sciences 126 20138767
2011 BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation. Cell death and differentiation 117 21738214
2008 Therapeutic potential of AIF-mediated caspase-independent programmed cell death. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 109 18180198
2015 Apoptosis-inducing Factor (AIF) and Its Family Member Protein, AMID, Are Rotenone-sensitive NADH:Ubiquinone Oxidoreductases (NDH-2). The Journal of biological chemistry 94 26063804
2020 MSC-derived exosomes attenuate cell death through suppressing AIF nucleus translocation and enhance cutaneous wound healing. Stem cell research & therapy 91 32393338
2019 AIF-regulated oxidative phosphorylation supports lung cancer development. Cell research 83 31133695
2021 Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy. Science translational medicine 82 33597260
2013 Role of AIF-1 in the regulation of inflammatory activation and diverse disease processes. Cellular immunology 81 23948156
2011 Mycotoxin zearalenone induces AIF- and ROS-mediated cell death through p53- and MAPK-dependent signaling pathways in RAW264.7 macrophages. Toxicology in vitro : an international journal published in association with BIBRA 81 21767629
2001 AIF-1 expression defines a proliferating and alert microglial/macrophage phenotype following spinal cord injury in rats. Journal of neuroimmunology 81 11585624
2012 AIF-mediated caspase-independent necroptosis requires ATM and DNA-PK-induced histone H2AX Ser139 phosphorylation. Cell death & disease 77 22972376
2010 Histone H2AX: The missing link in AIF-mediated caspase-independent programmed necrosis. Cell cycle (Georgetown, Tex.) 74 20697198
2003 AIF-1 is an actin-polymerizing and Rac1-activating protein that promotes vascular smooth muscle cell migration. Circulation research 69 12714565
2017 AIF-independent parthanatos in the pathogenesis of dry age-related macular degeneration. Cell death & disease 68 28055012
2021 OTUD1 Activates Caspase-Independent and Caspase-Dependent Apoptosis by Promoting AIF Nuclear Translocation and MCL1 Degradation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 67 33898171
2005 Cerebral endothelial cell apoptosis after ischemia-reperfusion: role of PARP activation and AIF translocation. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 66 15729291
2023 SIRT5-related desuccinylation modification of AIFM1 protects against compression-induced intervertebral disc degeneration by regulating mitochondrial homeostasis. Experimental & molecular medicine 58 36653443
2015 A novel AIFM1 mutation expands the phenotype to an infantile motor neuron disease. European journal of human genetics : EJHG 57 26173962
2005 BimEL up-regulation potentiates AIF translocation and cell death in response to MPTP. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 57 15941767
2016 Structure/Function Relations in AIFM1 Variants Associated with Neurodegenerative Disorders. Journal of molecular biology 55 27178839
2016 RIP3 induces ischemic neuronal DNA degradation and programmed necrosis in rat via AIF. Scientific reports 54 27377128
2006 Does apoptosis-inducing factor (AIF) have both life and death functions in cells? BioEssays : news and reviews in molecular, cellular and developmental biology 54 16927311
2011 Deletion of Cryptococcus neoformans AIF ortholog promotes chromosome aneuploidy and fluconazole-resistance in a metacaspase-independent manner. PLoS pathogens 52 22114551
2015 From ventriculomegaly to severe muscular atrophy: expansion of the clinical spectrum related to mutations in AIFM1. Mitochondrion 50 25583628
2007 Overcoming chemoresistance of non-small cell lung carcinoma through restoration of an AIF-dependent apoptotic pathway. Oncogene 50 17906690
2022 AIFM1 beyond cell death: An overview of this OXPHOS-inducing factor in mitochondrial diseases. EBioMedicine 49 35994922
2021 The mitochondrial protease LONP1 maintains oocyte development and survival by suppressing nuclear translocation of AIFM1 in mammals. EBioMedicine 48 34974310
2008 AIF-1 expression regulates endothelial cell activation, signal transduction, and vasculogenesis. American journal of physiology. Cell physiology 48 18787073
2020 AIF meets the CHCHD4/Mia40-dependent mitochondrial import pathway. Biochimica et biophysica acta. Molecular basis of disease 47 32105825
2012 AIF, reactive oxygen species, and neurodegeneration: a "complex" problem. Neurochemistry international 47 23246553
2020 Regulation of JNK signaling pathway and RIPK3/AIF in necroptosis-mediated global cerebral ischemia/reperfusion injury in rats. Experimental neurology 43 32502579
2017 X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1. Neurogenetics 43 28842795
2016 Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease. Clinical genetics 43 27102849
2015 Thioredoxin-dependent regulation of AIF-mediated DNA damage. Free radical biology & medicine 43 26119781
2016 Pristimerin triggers AIF-dependent programmed necrosis in glioma cells via activation of JNK. Cancer letters 42 26854718
2015 AIF inhibits tumor metastasis by protecting PTEN from oxidation. EMBO reports 42 26415504
2005 AIF and endoG translocation in noise exposure induced hair cell death. Hearing research 42 16309861
2018 AIF loss deregulates hematopoiesis and reveals different adaptive metabolic responses in bone marrow cells and thymocytes. Cell death and differentiation 41 29323266
2006 CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells. Oncogene 41 16636662
2004 AIF-1 expression modulates proliferation of human vascular smooth muscle cells by autocrine expression of G-CSF. Arteriosclerosis, thrombosis, and vascular biology 41 15117732
2022 AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5. The EMBO journal 40 35859387
2017 AIFM1 mutation presenting with fatal encephalomyopathy and mitochondrial disease in an infant. Cold Spring Harbor molecular case studies 40 28299359
2018 AIF-1 and RNASET2 Play Complementary Roles in the Innate Immune Response of Medicinal Leech. Journal of innate immunity 39 30368505
2011 Daintain/AIF-1 promotes breast cancer cell migration by up-regulated TNF-α via activate p38 MAPK signaling pathway. Breast cancer research and treatment 39 21509525
2022 Ubiquitinated AIF is a major mediator of hypoxia-induced mitochondrial dysfunction and pulmonary artery smooth muscle cell proliferation. Cell & bioscience 38 35090552
2018 Overexpression of apoptosis-inducing factor mitochondrion-associated 1 (AIFM1) induces apoptosis by promoting the transcription of caspase3 and DRAM in hepatoma cells. Biochemical and biophysical research communications 38 29501488
2018 A disease-associated Aifm1 variant induces severe myopathy in knockin mice. Molecular metabolism 34 29780003
2015 Caspase-3 feedback loop enhances Bid-induced AIF/endoG and Bak activation in Bax and p53-independent manner. Cell death & disease 33 26469967
2011 An alternative import pathway of AIF to the mitochondria. International journal of molecular medicine 33 22134679
2018 p53- and ROS-mediated AIF pathway involved in TGEV-induced apoptosis. The Journal of veterinary medical science 31 30249935
2017 A novel missense mutation in AIFM1 results in axonal polyneuropathy and misassembly of OXPHOS complexes. European journal of neurology 31 28888069
2017 Pioglitazone inhibits cancer cell growth through STAT3 inhibition and enhanced AIF expression via a PPARγ-independent pathway. Journal of cellular physiology 31 29030979
2016 mda-7/IL-24 Induces Cell Death in Neuroblastoma through a Novel Mechanism Involving AIF and ATM. Cancer research 31 27197168
2007 Down-regulation of human RNA/DNA helicase SUV3 induces apoptosis by a caspase- and AIF-dependent pathway. Biology of the cell 31 17352692
2023 p20BAP31 induces cell apoptosis via both AIF caspase-independent and the ROS/JNK mitochondrial pathway in colorectal cancer. Cellular & molecular biology letters 30 36977989
2004 Over-expression of AIF-1 in liver allografts and peripheral blood correlates with acute rejection after transplantation in rats. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 30 15575896
2019 Caspase/AIF/apoptosis pathway: a new target of puerarin for diabetes mellitus therapy. Molecular biology reports 28 31228042
2017 Structural and biochemical insights of CypA and AIF interaction. Scientific reports 28 28442737
2017 Frondoside A induces AIF-associated caspase-independent apoptosis in Burkitt lymphoma cells. Leukemia & lymphoma 28 28508718
2020 The human papillomavirus E6 protein targets apoptosis-inducing factor (AIF) for degradation. Scientific reports 27 32848167
2017 A newly distal hereditary motor neuropathy caused by a rare AIFM1 mutation. Neurogenetics 27 28975462
2012 Bnip3 and AIF cooperate to induce apoptosis and cavitation during epithelial morphogenesis. The Journal of cell biology 27 22753893
2020 Over-Expression of Allograft Inflammatory Factor-1 (AIF-1) in Patients with Rheumatoid Arthritis. Biomolecules 26 32708725
2024 Hyperglycemia-induced oxidative stress exacerbates mitochondrial apoptosis damage to cochlear stria vascularis pericytes via the ROS-mediated Bcl-2/CytC/AIF pathway. Redox report : communications in free radical research 25 39092597
2006 Immunohistochemical and mutational analysis of apoptosis-inducing factor (AIF) in colorectal carcinomas. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 25 17207087
2020 Mitochondrial AIF loss causes metabolic reprogramming, caspase-independent cell death blockade, embryonic lethality, and perinatal hydrocephalus. Molecular metabolism 24 32480041
2019 Downregulation of microRNA-425-5p suppresses cervical cancer tumorigenesis by targeting AIFM1. Experimental and therapeutic medicine 24 30988784
2016 Downregulation of AIF by HIF-1 contributes to hypoxia-induced epithelial-mesenchymal transition of colon cancer. Carcinogenesis 24 27543779
2018 Detergent Insoluble Proteins and Inclusion Body-Like Structures Immunoreactive for PRKDC/DNA-PK/DNA-PKcs, FTL, NNT, and AIFM1 in the Amygdala of Cognitively Impaired Elderly Persons. Journal of neuropathology and experimental neurology 22 29186589
2014 The expression of apoptosis inducing factor (AIF) is associated with aging-related cell death in the cortex but not in the hippocampus in the TgCRND8 mouse model of Alzheimer's disease. BMC neuroscience 21 24915960
2021 AIFM1, negatively regulated by miR-145-5p, aggravates hypoxia-induced cardiomyocyte injury. Biomedical journal 20 34863964
2020 High Frequency of AIFM1 Variants and Phenotype Progression of Auditory Neuropathy in a Chinese Population. Neural plasticity 20 32684920
2022 Nuclear Tkt promotes ischemic heart failure via the cleaved Parp1/Aif axis. Basic research in cardiology 19 35380314
2025 Apoptosis-inducing factor (AIF) at the crossroad of cell survival and cell death: implications for cancer and mitochondrial diseases. Cell communication and signaling : CCS 18 40468311
2021 RIP3 facilitates necroptosis through CaMKII and AIF after intracerebral hemorrhage in mice. Neuroscience letters 18 33540056
2021 PAK5-mediated AIF phosphorylation inhibits its nuclear translocation and promotes breast cancer tumorigenesis. International journal of biological sciences 18 33867848
2023 Impaired AIF-CHCHD4 interaction and mitochondrial calcium overload contribute to auditory neuropathy spectrum disorder in patient-iPSC-derived neurons with AIFM1 variant. Cell death & disease 17 37365177

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