ArticleThe EMBO journal2010
AIF promotes chromatinolysis and caspase-independent programmed necrosis by interacting with histone H2AX.
Article in The EMBO journal, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers.
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Who cites it
119 citing papers in PubMed, 214 citations in OpenAlex.
- Integrated Necroptosis Within Programmed Cell Death in Traumatic Brain Injury.Molecular neurobiology · 2026Review
- Potential causal role of mitochondrial biological effects in COVID-19: Evidence from Mendelian randomization study.Medicine · 2026Article
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- Clinical and molecular characterization of a novel pathogenic AIFM1 E336K mutation connecting mitochondrial dysfunction and neurodegeneration.Cell communication and signaling : CCS · 2026Article
- The role of nGPx4 in resisting DEHP-induced DNA damage and reducing caspase-independent cell death in male germ cells.Clinical and experimental reproductive medicine · 2026Article
- PARP1 Suppression Drives ROS Resistance in Aneuploid Cancer Cells.bioRxiv : the preprint server for biology · 2026Article
- Reactive Oxygen Species Across Death Pathways: Gatekeepers of Apoptosis, Ferroptosis, Pyroptosis, Paraptosis, and Beyond.International journal of molecular sciences · 2025Review
- Review
- Deacetylation of nuclear AIF provides a braking mechanism for caspase-independent chromatinolysis and necrotic brain injury.Communications biology · 2025Article
- Inducing Targeted, Caspase-Independent Apoptosis with New Chimeric Proteins for Treatment of Solid Cancers.Cancers · 2025Article
- The Function of H2A Histone Variants and Their Roles in Diseases.Biomolecules · 2024Review
- The Role of Necroptosis in Cerebral Ischemic Stroke.Molecular neurobiology · 2024Review
- AIF translocation into nucleus caused by Aifm1 R450Q mutation: generation and characterization of a mouse model for AUNX1.Human molecular genetics · 2024Article
- Molecular mechanisms of cell death by parthanatos: More questions than answers.Genetics and molecular biology · 2024Article
- Therapeutic and preventive effects of astaxanthin in ischemic stroke.Frontiers in nutrition · 2024Review
- Non-apoptotic regulated cell death in Fuchs endothelial corneal dystrophy.Regenerative therapy · 2023Article
- Article
- Cynaropicrin disrupts tubulin and c-Myc-related signaling and induces parthanatos-type cell death in multiple myeloma.Acta pharmacologica Sinica · 2023Article
- Mitochondrial Factors in the Cell Nucleus.International journal of molecular sciences · 2023Review
- TAX1BP1 contributes to deoxypodophyllotoxin-induced glioma cell parthanatos via inducing nuclear translocation of AIF by activation of mitochondrial respiratory chain complex I.Acta pharmacologica Sinica · 2023Article
59 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Programmed necrosis induced by DNA alkylating agents, such as MNNG, is a caspase-independent mode of cell death mediated by apoptosis-inducing factor (AIF). After poly(ADP-ribose) polymerase 1, calpain, and Bax activation, AIF moves from the mitochondria to the nucleus where it induces chromatinolysis and cell death. The mechanisms underlying the nuclear action of AIF are, however, largely unknown. We show here that, through its C-terminal proline-rich binding domain (PBD, residues 543-559), AIF associates in the nucleus with histone H2AX. This interaction regulates chromatinolysis and programmed necrosis by generating an active DNA-degrading complex with cyclophilin A (CypA). Deletion or directed mutagenesis in the AIF C-terminal PBD abolishes AIF/H2AX interaction and AIF-mediated chromatinolysis. H2AX genetic ablation or CypA downregulation confers resistance to programmed necrosis. AIF fails to induce chromatinolysis in H2AX or CypA-deficient nuclei. We also establish that H2AX is phosphorylated at Ser139 after MNNG treatment and that this phosphorylation is critical for caspase-independent programmed necrosis. Overall, our data shed new light in the mechanisms regulating programmed necrosis, elucidate a key nuclear partner of AIF, and uncover an AIF apoptogenic motif.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.