# Mitochondrial outer membrane permeabilization
**Mitochondrial outer membrane permeabilization (MOMP)** is the increase in permeability of the mitochondrial outer membrane during apoptosis, permitting the release of soluble molecules, such as proteins, from the intermembrane space into the cytosol[1](https://www.sciencedirect.com/science/article/pii/S0304419X25000228) • [16](https://pmc.ncbi.nlm.nih.gov/articles/PMC6120664/). It is the pivotal event of the intrinsic, or mitochondrial, pathway of apoptosis: the released intermembrane space proteins, above all cytochrome c, promote activation of the caspase proteases that dismantle the cell[2](https://doi.org/10.1038/nrm2952). MOMP is controlled primarily by interactions between pro-apoptotic and anti-apoptotic members of the [B cell](https://www.edgepedia.org/b-cell) lymphoma 2 (BCL-2) protein family, and it is generally regarded as a point of no return in cell death signaling[2](https://doi.org/10.1038/nrm2952) • [3](https://journals.biologists.com/jcs/article/122/16/2801/30679/Mechanisms-by-which-Bak-and-Bax-permeabilise).
| Key fact | Detail |
|---|---|
| Definition | Increased permeability of the mitochondrial outer membrane, releasing intermembrane space proteins such as cytochrome c and SMAC into the cytosol[1](https://www.sciencedirect.com/science/article/pii/S0304419X25000228) • [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC5578938/) |
| Effectors | The pro-apoptotic BCL-2 proteins BAX and BAK are required for MOMP; mice lacking both show severely impaired apoptosis during development[2](https://doi.org/10.1038/nrm2952) • [3](https://journals.biologists.com/jcs/article/122/16/2801/30679/Mechanisms-by-which-Bak-and-Bax-permeabilise) |
| Downstream cascade | Cytochrome c binds APAF1, triggering apoptosome assembly and caspase-9 activation, which activates caspase-3 and caspase-7; SMAC release blocks the caspase inhibitor XIAP[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC5578938/) |
| Commitment to death | MOMP typically kills the cell even without caspase activity, through caspase-independent cell death driven by progressive loss of mitochondrial function[2](https://doi.org/10.1038/nrm2952) |
| Pore mechanism | The precise nature of the apoptotic pore is unknown but is probably lipidic; a mitochondrial outer membrane protein factor termed the catalyst adds a further layer of regulation[5](https://pubmed.ncbi.nlm.nih.gov/24453042/) |
| Coupling to function | MOMP is tightly coupled with loss of the mitochondrial membrane potential ΔΨm, which sustains ATP production[6](https://www.sciencedirect.com/science/article/pii/S1084952123001416) |
| Clinical relevance | Targeting MOMP with BCL-2 inhibitors such as the FDA-approved venetoclax restores death sensitivity in cancer cells[7](https://www.jci.org/articles/view/179570) • [1](https://www.sciencedirect.com/science/article/pii/S0304419X25000228) |
## Role in the intrinsic apoptotic pathway
The intrinsic pathway is activated by a range of cellular stresses, including DNA damage, lysosomal and endoplasmic reticulum stress, metabolic stress, ionizing radiation, heat, hypoxia, cytokine deprivation, and chemotherapeutic drugs[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC5578938/). These stresses funnel through the BCL-2 family to the mitochondrial outer membrane, where BAX and BAK activation culminates in permeabilization[3](https://journals.biologists.com/jcs/article/122/16/2801/30679/Mechanisms-by-which-Bak-and-Bax-permeabilise).
Once the outer membrane is breached, cytochrome c, a heme protein that normally has a crucial role in respiration, enters the cytosol and binds apoptotic protease activating factor 1 (APAF1). This triggers apoptosome assembly and activation of the initiator caspase-9, which in turn activates the executioner caspases 3 and 7[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC5578938/) • [8](https://www.nature.com/articles/cdd2017179). Release of second mitochondria-derived activator of caspases (SMAC) facilitates apoptosis by blocking the caspase inhibitor X-linked inhibitor of apoptosis protein (XIAP)[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC5578938/). Following permeabilization, caspases are activated robustly, typically within a few minutes[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC3753705/).
The extrinsic pathway, triggered by cell-surface death receptors, can activate caspases without mitochondria, but in certain cell types it also engages MOMP: caspase-8 cleaves the BH3-only protein BID to its truncated form tBID, which activates BAK and BAX and enables crosstalk between the two pathways[3](https://journals.biologists.com/jcs/article/122/16/2801/30679/Mechanisms-by-which-Bak-and-Bax-permeabilise) • [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC5578938/).
## Control by the BCL-2 family
Mitochondrial outer membrane integrity is dynamically regulated through interactions between pro- and anti-apoptotic BCL-2 family members[2](https://doi.org/10.1038/nrm2952). The family falls into three functional subclasses: pro-survival proteins, pro-apoptotic BH3-only proteins that initiate the pathway, and the effectors BAX and BAK (and possibly BOK), which act downstream of both[3](https://journals.biologists.com/jcs/article/122/16/2801/30679/Mechanisms-by-which-Bak-and-Bax-permeabilise).
Upon apoptotic stimuli, BAX and BAK change conformation when activated by BH3 domain-only proteins and oligomerize at the outer membrane to permeabilize it, while pro-survival members inhibit this process[5](https://pubmed.ncbi.nlm.nih.gov/24453042/). A key step in BAK activation is transient exposure of its BH3 domain, which binds the hydrophobic groove of another activated BAK molecule to form a novel symmetric dimer; the dimers then associate through a secondary interface to build the higher-order oligomers that probably constitute the pore complex[3](https://journals.biologists.com/jcs/article/122/16/2801/30679/Mechanisms-by-which-Bak-and-Bax-permeabilise). BAX, which in healthy cells is restrained in the cytosol by a transmembrane-to-groove interaction and by retrotranslocation promoted by Bcl-xL, translocates to the outer membrane during activation[3](https://journals.biologists.com/jcs/article/122/16/2801/30679/Mechanisms-by-which-Bak-and-Bax-permeabilise) • [10](https://pmc.ncbi.nlm.nih.gov/articles/PMC3579396/).
The membrane environment itself participates in regulation. Outer membrane lipids and resident proteins such as VDAC, hexokinase, and MTCH2 regulate BAX/BAK activation, and a protein factor termed the catalyst in the outer membrane is needed for BAX and BAK to achieve efficient and complete permeabilization[11](https://www.sciencedirect.com/science/article/pii/S0005273621001644) • [5](https://pubmed.ncbi.nlm.nih.gov/24453042/). Mitochondrial dynamics do not affect MOMP directly but appear closely coordinated with it for swift protein efflux[5](https://pubmed.ncbi.nlm.nih.gov/24453042/).
## The apoptotic pore
How BAX and BAK permeabilize the membrane remains unresolved[2](https://doi.org/10.1038/nrm2952). The pore complexes they form are poorly defined in composition, size, number, and structure[3](https://journals.biologists.com/jcs/article/122/16/2801/30679/Mechanisms-by-which-Bak-and-Bax-permeabilise). The precise nature of the apoptotic pore is unknown but is probably lipidic[5](https://pubmed.ncbi.nlm.nih.gov/24453042/). Nanodisc experiments suggest that when BAX binds membranes it unfolds on the surface in an umbrella-like conformation that is not compatible with a protein-lined pore, and some kinetic measurements indicate BAX monomers, not oligomers, are rate-limiting, although membrane-bound BAX oligomers can auto-activate monomeric soluble BAX[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC3890960/). Structural work shows the oligomers are heterogeneous, with pores that can be partially or fully lined by BAX molecules[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC5898608/). The mitochondrial apoptosis-induced channel (MAC) model has been ruled out as the mediator, because MOMP releases both small and large molecules whereas MAC only allows limited molecule sizes to pass[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC5578938/).
## Consequences: caspase-dependent and caspase-independent death
MOMP kills through a twofold attack: it initiates the caspase proteolytic cascade and it damages mitochondrial function[3](https://journals.biologists.com/jcs/article/122/16/2801/30679/Mechanisms-by-which-Bak-and-Bax-permeabilise). Even when caspase activation is disrupted or blocked, cells engaged in the mitochondrial pathway generally still die, a mode termed caspase-independent cell death (CICD)[14](https://pmc.ncbi.nlm.nih.gov/articles/PMC9159267/). CICD occurs through a progressive decline in mitochondrial function and is generally slower than apoptosis, resembling necrosis in that the cell dies from loss of mitochondrial function[2](https://doi.org/10.1038/nrm2952) • [3](https://journals.biologists.com/jcs/article/122/16/2801/30679/Mechanisms-by-which-Bak-and-Bax-permeabilise). [Genetic ablation](https://www.edgepedia.org/genetic-ablation) of apaf1 or caspase9 delays death but does not prevent loss of clonogenicity[3](https://journals.biologists.com/jcs/article/122/16/2801/30679/Mechanisms-by-which-Bak-and-Bax-permeabilise). This dual mechanism is why MOMP is often considered the point of no return, and prevention of MOMP can rescue cells from death[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC3753705/) • [3](https://journals.biologists.com/jcs/article/122/16/2801/30679/Mechanisms-by-which-Bak-and-Bax-permeabilise).
## Survival after MOMP and limited MOMP
Under some circumstances cells survive MOMP. Survival requires a pool of mitochondria that remain intact after the event and is promoted by glycolysis and autophagy[2](https://doi.org/10.1038/nrm2952). The severity of MOMP varies: minor MOMP (miMOMP) allows survival, while complete MOMP causes cell death[1](https://www.sciencedirect.com/science/article/pii/S0304419X25000228).
**Limited MOMP has pathophysiological consequences.** In limited MOMP, mammalian cells initiate the intrinsic apoptosis pathway with increased mitochondrial permeability but survive[15](https://link.springer.com/article/10.1186/s13578-020-00442-y). Sublethal MOMP causes cytosolic leakage of cytochrome c and sublethal activation of caspases 3, 6, and 7 and of the endonucleases CAD and endoG, producing persistent DNA double strand breaks[15](https://link.springer.com/article/10.1186/s13578-020-00442-y). These self-inflicted breaks activate the DNA damage response, including ATM phosphorylation, and have been linked to malignant transformation, radiation- and chemical-induced carcinogenesis, and maintenance of cancer stemness; in one study, limited MOMP accounted for at least 50% of DNA double strand breaks in tumor cells as measured by γH2AX foci[15](https://link.springer.com/article/10.1186/s13578-020-00442-y). Sublethal MOMP more broadly can lead to senescence, drug resistance, and genomic instability[1](https://www.sciencedirect.com/science/article/pii/S0304419X25000228).
## Clinical relevance
Because the intrinsic pathway is often deregulated in cancer, MOMP has become a therapeutic target[8](https://www.nature.com/articles/cdd2017179). Anti-cancer agents that target the BCL-2 protein family show considerable promise, and the BCL-2 inhibitor venetoclax has been approved by the US FDA[3](https://journals.biologists.com/jcs/article/122/16/2801/30679/Mechanisms-by-which-Bak-and-Bax-permeabilise) • [7](https://www.jci.org/articles/view/179570). Targeting MOMP with BCL-2 inhibitors restores cancer cell death sensitivity, and including outer membrane lipid and protein interactions in BH3-mimetic design may improve efficacy[1](https://www.sciencedirect.com/science/article/pii/S0304419X25000228) • [11](https://www.sciencedirect.com/science/article/pii/S0005273621001644).
## References
1. [Liu D, Liu Z, Hu Y, Xiong W, Wang D, Zeng Z (2025). MOMP: A critical event in cell death regulation and anticancer treatment. Biochimica et Biophysica Acta - Reviews on Cancer.](https://www.sciencedirect.com/science/article/pii/S0304419X25000228)
2. [Tait SWG, Green DR (2010). Mitochondria and cell death: outer membrane permeabilization and beyond. Nature Reviews Molecular Cell Biology 11:621–632.](https://doi.org/10.1038/nrm2952)
3. [Dewson G, Kluck RM (2009). Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis. Journal of Cell Science 122:2801–2808.](https://journals.biologists.com/jcs/article/122/16/2801/30679/Mechanisms-by-which-Bak-and-Bax-permeabilise)
4. [Mitochondrial outer membrane permeabilization: a focus on the role of mitochondrial membrane structural organization. PMC.](https://pmc.ncbi.nlm.nih.gov/articles/PMC5578938/)
5. [Apoptosis regulation at the mitochondrial outer membrane. PubMed.](https://pubmed.ncbi.nlm.nih.gov/24453042/)
6. [Shedding light on mitochondrial outer-membrane permeabilization and membrane potential: State of the art methods and biosensors. Seminars in Cell & Developmental Biology 156:58–65 (2024).](https://www.sciencedirect.com/science/article/pii/S1084952123001416)
7. [Targeting apoptotic pathways for cancer therapy. Journal of Clinical Investigation.](https://www.jci.org/articles/view/179570)
8. [Kalkavan H, Green DR (2018). MOMP, cell suicide as a BCL-2 family business. Cell Death & Differentiation 25:46–55.](https://www.nature.com/articles/cdd2017179)
9. [Mitochondrial Regulation of Cell Death. PMC.](https://pmc.ncbi.nlm.nih.gov/articles/PMC3753705/)
10. [Where Killers Meet—Permeabilization of the Outer Mitochondrial Membrane during Apoptosis. PMC.](https://pmc.ncbi.nlm.nih.gov/articles/PMC3579396/)
11. [Dadsena S, King LE, García-Sáez AJ (2021). Apoptosis regulation at the mitochondria membrane level. BBA - Biomembranes 1863(12):183716.](https://www.sciencedirect.com/science/article/pii/S0005273621001644)
12. [The apoptotic pore on mitochondria: are we breaking through or still stuck? PMC.](https://pmc.ncbi.nlm.nih.gov/articles/PMC3890960/)
13. [Bax and Bak Pores: Are We Closing the Circle? PMC.](https://pmc.ncbi.nlm.nih.gov/articles/PMC5898608/)
14. [The Mitochondrial Pathway of Apoptosis: Part I: MOMP and Beyond. PMC.](https://pmc.ncbi.nlm.nih.gov/articles/PMC9159267/)
15. [Bao X, Liu X, Li F, Li C-Y (2020). Limited MOMP, ATM, and their roles in carcinogenesis and cancer treatment. Cell & Bioscience 10:81.](https://link.springer.com/article/10.1186/s13578-020-00442-y)
16. [pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6120664/)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Enzyme classes and activities › Proteolytic and peptidase enzymes › Proteases by catalytic mechanism › Cysteine proteases › Caspases and apoptotic proteolysis › Caspase activation pathways*
*Initially written Sep 17, 2026 · Reviewed: Sep 30, 2026; Oct 21, 2026 · Edited: Sep 30, 2026; Oct 11, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license