ArticleMolecular cell2009
Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis.
Article in Molecular cell, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 358 papers.
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Who cites it
358 citing papers in PubMed, 575 citations in OpenAlex.
- Jaceidin Inhibits Proliferation and Promotes Apoptosis in Oral Squamous Cell Carcinoma Cells by Regulating Survivin and AKT/ERK Signaling Pathways.International journal of molecular sciences · 2026Article
- Direct binding of the C-terminal sequences of Bim and Bak contributes to efficient Bak activation.Cell death and differentiation · 2026Article
- Dual targeting of BCL-XL and MCL-1 exposes a rapid and exploitable apoptotic vulnerability in non-small cell lung cancer.Cell death and differentiation · 2026Article
- Reverse engineering of BNIP3 identifies a mitochondrial protective peptide.Nature communications · 2026Article
- Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.Muscles (Basel, Switzerland) · 2026Review
- Deciphering Bax Dynamics: Regulation, Retrotranslocation, and Mitochondrial Interplay in the Commitment to Apoptosis: A Narrative Review.Health science reports · 2026Article
- Mitochondrial-Based Nanomedicine in Treatment of Liver Cancer.Molecular biotechnology · 2026Review
- A gated hydrophobic funnel within BAX binds bioactive lipids to potentiate pro-apoptotic function.Nature communications · 2026Article
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- The interplay between circadian rhythm components and apoptosis in health and disease.Human cell · 2026Review
- Short term ex vivo graft conditioning with venetoclax, fluticasone propionate, and IL-2 reduces graft versus host disease in mouse allogeneic hematopoietic cell transplantation.Frontiers in immunology · 2026Article
- BAK and BAX: Therapeutic Targets for Acute Myocardial Infarction and Myocardial Ischemia-Reperfusion Injury.Biology · 2025Review
- Multifaceted Roles of Bcl-2 Family Proteins: Regulatory Roles in Apoptosis, Physiological Functions, and Therapeutic Potential.Current medical science · 2025Review
- Endoplasmic reticulum stress-related genes contribute to lung cancer risk: a multiomics data integration study.Translational lung cancer research · 2025Article
- Nesprin-2 contains BH3-like motifs that can promote cell death.Cell death discovery · 2025Article
- Collaborative orchestration of BH3-only proteins governs Bak/Bax-dependent hepatocyte apoptosis under antiapoptotic protein-deficiency in mice.Cell death and differentiation · 2025Article
- MnTBAP, a peroxynitrite scavenger, attenuates cisplatin-induced apoptosis and cytotoxicity in organ of Corti cells.Toxicology reports · 2025Article
- Apolipoprotein A1 deficiency increases macrophage apoptosis and necrotic core development in atherosclerotic plaques in a Bim-dependent manner.Journal of lipid research · 2025Article
- Review
298 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
While activation of BAX/BAK by BH3-only molecules (BH3s) is essential for mitochondrial apoptosis, the underlying mechanisms remain unsettled. Here we demonstrate that BAX undergoes stepwise structural reorganization leading to mitochondrial targeting and homo-oligomerization. The alpha1 helix of BAX keeps the alpha9 helix engaged in the dimerization pocket, rendering BAX as a monomer in cytosol. The activator BH3s, tBID/BIM/PUMA, attack and expose the alpha1 helix of BAX, resulting in secondary disengagement of the alpha9 helix and thereby mitochondrial insertion. Activator BH3s remain associated with the N-terminally exposed BAX through the BH1 domain to drive homo-oligomerization. BAK, an integral mitochondrial membrane protein, has bypassed the first activation step, explaining why its killing kinetics are faster than those of BAX. Furthermore, death signals initiated at ER induce BIM and PUMA to activate mitochondrial apoptosis. Accordingly, deficiency of Bim/Puma impedes ER stress-induced BAX/BAK activation and apoptosis. Our study provides mechanistic insights regarding the spatiotemporal execution of BAX/BAK-governed cell death.
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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.