GO:1902110 positive regulation of mitochondrial membrane permeability involved in apoptotic process: Apoptotic Pore Opening, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1902110 describes the biological process that increases mitochondrial membrane permeability specifically as part of apoptosis, often called mitochondrial outer membrane permeabilization (MOMP) or the mitochondrial permeability transition (MPT).
• Opening of the permeability transition pore (PTP) or Bax/Bak pore allows release of cytochrome c and other intermembrane proteins, which triggers caspase activation and cell death.
• Key regulators include BCL-2 family proteins, the PTP component VDAC/ANT, and signaling kinases such as PI3K/Akt/GSK-3beta that modulate pore opening.
• Pharmacological modulators of multidrug resistance and natural compounds can directly influence PTP opening, linking this process to cancer therapy and chemoresistance.
• Dysregulated mitochondrial permeabilization contributes to ischemia-reperfusion injury, cardiomyocyte death, and neurodegenerative conditions, making it a therapeutic target.
• CRISPR knockout, point-mutation, knock-in, and overexpression models are essential to dissect which genes causally regulate this process in disease-relevant cell types.
Description
The Gene Ontology term GO:1902110, positive regulation of mitochondrial membrane permeability involved in apoptotic process, defines any biological activity that increases the permeability of mitochondrial membranes as part of the apoptotic program. Mitochondria are bounded by an outer membrane (OMM) and an inner membrane (IMM); under apoptotic stimuli, these barriers become leaky, allowing soluble intermembrane space proteins such as cytochrome c to enter the cytosol and initiate caspase activation. This process is often referred to as mitochondrial outer membrane permeabilization (MOMP) or the mitochondrial permeability transition (MPT), and it represents a point of no return in many intrinsic apoptotic pathways. Researchers study GO:1902110 because it sits at the intersection of cell death regulation, metabolism, and disease. The permeability transition pore (PTP) is a large, multi-protein channel whose opening is favored by calcium overload, oxidative stress, and low membrane potential, and is inhibited by cyclophilin D ligands and certain multidrug resistance modulators. In cancer, evasion of MOMP/MPT contributes to chemoresistance, while in ischemia-reperfusion injury, excessive pore opening drives necrotic and apoptotic tissue damage. Understanding which genes positively regulate this process is therefore central to developing targeted therapies. The term is defined in QuickGO as any positive regulation of mitochondrial membrane permeability that is involved in apoptotic process. It is a biological_process child of mitochondrial membrane permeability regulation and is synonymous with mitochondrial membrane permeabilization involved in apoptosis, mitochondrial permeability transition involved in apoptosis, and positive regulation of transport across mitochondrial membrane involved in apoptosis. Because the process is highly context-dependent, experimental models ranging from CRISPR knockout cells to patient-derived organoids are used to identify the molecular players and their causal roles.
positive regulation of mitochondrial membrane permeability involved in apoptotic process At A Glance
| GO ID | GO:1902110 |
|---|---|
| GO term | positive regulation of mitochondrial membrane permeability involved in apoptotic process |
| Ontology | biological_process |
| Synonym | mitochondrial membrane permeabilization involved in apoptosis; mitochondrial permeability transition involved in apoptosis; positive regulation of transport across mitochondrial membrane involved in apoptosis |
| Major function | Increases mitochondrial membrane permeability to release pro-apoptotic factors and commit the cell to apoptosis |
| Parent term | regulation of mitochondrial membrane permeability |
| Related process | intrinsic apoptotic signaling pathway; mitochondrial outer membrane permeabilization (MOMP); mitochondrial permeability transition (MPT) |
| Key cellular location | mitochondrial outer membrane, inner membrane, and intermembrane space |
| Disease relevance | cancer chemoresistance, ischemia-reperfusion injury, cardiomyocyte death, neurodegeneration |
What Is GO:1902110?
GO:1902110 is a biological process term that covers any molecular event or signaling activity that increases the permeability of mitochondrial membranes specifically during apoptosis. It includes opening of the mitochondrial permeability transition pore (PTP), Bax/Bak-mediated outer membrane pore formation, and related transport changes that allow release of pro-apoptotic factors such as cytochrome c. The term is not about baseline mitochondrial permeability but about the regulated, apoptosis-associated increase that commits a cell to death.
Why Is positive regulation of mitochondrial membrane permeability involved in apoptotic process Important in Cell Biology?
GO:1902110 is important because mitochondrial membrane permeabilization is a decisive step in intrinsic apoptosis and a major determinant of cell fate in health and disease. Pharmacological or genetic modulation of this process can sensitize cancer cells to chemotherapy, protect cardiomyocytes from ischemia-reperfusion injury, or influence inflammatory cell death pathways. Because the process is regulated by BCL-2 family proteins, kinases, and metabolic signals, it offers multiple entry points for therapeutic intervention and is a frequent focus of CRISPR-based functional genomics screens.
• Defines the point of no return in intrinsic apoptosis, making it a central node in cell death research.
• Directly controls release of cytochrome c and other intermembrane proteins that activate caspases.
• Modulated by BCL-2 family proteins, PTP components, and signaling kinases such as PI3K/Akt/GSK-3beta.
• Contributes to chemoresistance in hepatocellular carcinoma and colorectal cancer models.
• Drives cardiomyocyte death in ischemia-reperfusion injury and heart failure models.
• Linked to inflammatory cell death and mitochondrial DNA release in intestinal ischemia-reperfusion injury.
• Target of natural compounds and multidrug resistance modulators that alter PTP opening.
• Provides a functional readout for CRISPR screens aimed at identifying apoptosis regulators.
• Relevant to neurodegenerative diseases where aberrant mitochondrial permeabilization contributes to neuronal loss.
• Enables development of organelle-specific biosensors and imaging assays for live-cell apoptosis monitoring.
What Happens During positive regulation of mitochondrial membrane permeability involved in apoptotic process?
Initiation by apoptotic stimuli and calcium overload
In simple terms: A stress signal or too much calcium inside the cell tells the mitochondria to become leaky.
Apoptotic stimuli such as DNA damage, oxidative stress, or calcium overload trigger signaling cascades that converge on mitochondria. Calcium uptake into the mitochondrial matrix can sensitize the permeability transition pore (PTP), while pro-apoptotic BCL-2 family proteins such as Bax and Bak are activated and translocate to the outer membrane. In hepatocellular carcinoma cells, inhibition of the PI3K/Akt/GSK-3beta pathway facilitates PTP opening, showing that survival kinase signaling directly restrains this initiation step.
Pore formation and membrane permeabilization
In simple terms: Channels open in the mitochondrial membranes, making them leaky.
Once activated, Bax/Bak oligomerize and form pores in the mitochondrial outer membrane, while the PTP can open at the inner membrane. This increases permeability to ions and small molecules, causing mitochondrial swelling and rupture of the outer membrane. Multidrug resistance modulators can influence PTP opening, indicating that transport proteins and membrane lipid composition contribute to pore regulation. In colorectal cancer, sanguinarine triggers intrinsic apoptosis through a mechanism involving dissociation of STRAP and MELK, which leads to mitochondrial permeabilization.
Release of pro-apoptotic factors
In simple terms: Proteins that tell the cell to die leak out of the mitochondria into the cytoplasm.
Permeabilization allows release of cytochrome c, SMAC/DIABLO, and other intermembrane space proteins into the cytosol. Cytochrome c binds APAF-1 to form the apoptosome, which activates initiator caspase-9 and downstream executioner caspases. In intestinal ischemia-reperfusion injury, mitochondrial DNA release following permeabilization can trigger pyroptosis through TRIM25-mediated pathways, linking mitochondrial leakage to inflammatory cell death.
Feedback amplification and commitment to apoptosis
In simple terms: Once the mitochondria leak, the death signal amplifies and the cell commits to dying.
Caspase activation further amplifies mitochondrial permeabilization through feedback loops involving Bid cleavage and additional Bax/Bak activation. This commitment step is regulated by anti-apoptotic BCL-2 proteins such as BCL-2 and BCL-xL, which can inhibit pore formation. In cardiomyocytes, ferroptosis-mitochondrial crosstalk can amplify death signals, and NRIP1 has been implicated in OGD/R-induced mitochondrial dysfunction in H9c2 cells.
Key Genes Involved in GO:1902110 positive regulation of mitochondrial membrane permeability involved in apoptotic process
The following genes and proteins are experimentally implicated in the regulation of mitochondrial membrane permeability during apoptosis, based on the verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| TP53 | Activates pro-apoptotic BCL-2 family members and sensitizes mitochondria to permeabilization | Frequently mutated in cancers; CRISPR KO models study apoptosis evasion |
| BAX | Forms pores in the mitochondrial outer membrane during MOMP | Central effector of intrinsic apoptosis; knockout cells are resistant to many apoptotic stimuli |
| BAK | Cooperates with BAX to permeabilize the outer membrane | BAX/BAK double knockout is a gold-standard model for MOMP deficiency |
| BCL2 | Anti-apoptotic protein that inhibits BAX/BAK pore formation | Overexpression models study chemoresistance; target of venetoclax |
| BCL2L1 | Encodes BCL-xL, inhibits mitochondrial permeabilization | Knockout or knockdown sensitizes cells to apoptosis |
| VDAC1 | Voltage-dependent anion channel involved in metabolite transport and PTP regulation | Modulates PTP opening; studied in cancer metabolism |
| PPIF | Encodes cyclophilin D, a key PTP regulator | Genetic deletion or pharmacological inhibition blocks MPT |
| ANT1 (SLC25A4) | Adenine nucleotide translocator, a proposed PTP component | Isoform-specific roles in MPT are studied with knockout models |
| GSK3B | Kinase that modulates PTP opening downstream of PI3K/Akt | Inhibition facilitates PTP opening in hepatocellular carcinoma |
| PIK3CA | PI3K catalytic subunit that promotes survival signaling and inhibits PTP opening | Mutations affect apoptosis sensitivity; studied with CRISPR knock-in |
| AKT1 | Survival kinase that phosphorylates targets to inhibit mitochondrial permeabilization | Constitutively active mutants protect cells from apoptosis |
| STRAP | Scaffold protein that interacts with MELK and influences apoptosis | Disruption by sanguinarine triggers intrinsic apoptosis in colorectal cancer |
| MELK | Kinase implicated in apoptosis regulation and mitochondrial permeabilization | Target of natural compounds; studied in cancer cell lines |
| TRIM25 | E3 ubiquitin ligase that triggers pyroptosis through mitochondrial DNA release | Knockout models study ischemia-reperfusion injury |
| NRIP1 | Nuclear receptor interacting protein 1, downstream of YY1, promotes mitochondrial dysfunction | Knockdown protects H9c2 cardiomyocytes from OGD/R injury |
| YY1 | Transcription factor that regulates NRIP1 and mitochondrial dysfunction | Studied in cardiomyocyte ischemia-reperfusion models |
| CYPD (PPIF) | Cyclophilin D, PTP regulator | Target of cyclosporin A analogs; knockout mice are protected from MPT-driven necrosis |
| SLC25A4 | ANT1, inner membrane transporter | Mutations linked to mitochondrial disease; models study PTP gating |
How Is positive regulation of mitochondrial membrane permeability involved in apoptotic process Regulated?
The process is regulated at multiple levels. Survival kinases such as PI3K/Akt and GSK-3beta phosphorylate downstream targets to inhibit or promote PTP opening; inhibition of PI3K/Akt/GSK-3beta signaling facilitates PTP opening in hepatocellular carcinoma cells. BCL-2 family proteins provide a rheostat: anti-apoptotic BCL-2/BCL-xL inhibit pore formation, while pro-apoptotic BAX/BAK promote it. Calcium and reactive oxygen species sensitize the PTP, whereas cyclophilin D inhibitors and certain multidrug resistance modulators can block opening. In cardiomyocytes, NRIP1 downstream of YY1 promotes mitochondrial dysfunction under OGD/R conditions, indicating transcriptional control of this process. Ferroptosis-mitochondrial crosstalk also modulates mitochondrial permeabilization in cardiomyocyte death.
positive regulation of mitochondrial membrane permeability involved in apoptotic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| GSK3B | Hepatocellular carcinoma chemoresistance | CRISPR knockout or point-mutation in HepG2 cells followed by PTP assays |
| STRAP/MELK | Colorectal cancer growth and apoptosis | Knockout or overexpression in HCT116 cells treated with sanguinarine |
| TRIM25 | Intestinal ischemia-reperfusion injury and pyroptosis | Knockout mice or intestinal organoids with mitochondrial DNA release assays |
| NRIP1/YY1 | Cardiomyocyte ischemia-reperfusion injury | H9c2 cardiomyocyte knockout or knockdown under OGD/R |
| PPIF (Cyclophilin D) | Mitochondrial permeability transition-driven necrosis | PPIF knockout mice or cells treated with cyclosporin A analogs |
Cancer chemoresistance and apoptosis evasion
Many cancers evade apoptosis by upregulating anti-apoptotic BCL-2 proteins or downregulating BAX/BAK, reducing mitochondrial membrane permeabilization. In hepatocellular carcinoma, inhibition of PI3K/Akt/GSK-3beta facilitates PTP opening and promotes cell death, suggesting that survival kinase signaling restrains this process. In colorectal cancer, sanguinarine triggers intrinsic apoptosis through dissociation of STRAP and MELK, leading to mitochondrial permeabilization and tumor suppression. Modulators of multidrug resistance can also influence PTP opening, linking drug efflux and mitochondrial permeabilization.
Ischemia-reperfusion injury and cardiomyocyte death
During ischemia-reperfusion, calcium overload and oxidative stress promote PTP opening, causing cardiomyocyte death. TRIM25 triggers pyroptosis through mitochondrial DNA release in intestinal ischemia-reperfusion injury, demonstrating a link between mitochondrial permeabilization and inflammatory cell death. In H9c2 cardiomyocytes subjected to oxygen-glucose deprivation/reoxygenation, NRIP1 downstream of YY1 promotes mitochondrial dysfunction, and knockdown of NRIP1 is protective. Ferroptosis-mitochondrial crosstalk further amplifies cardiomyocyte death in proposed frameworks.
Neurodegeneration and mitochondrial dysfunction
Aberrant mitochondrial membrane permeabilization contributes to neuronal loss in neurodegenerative diseases. Although direct evidence in the verified citations is limited, the general mechanism of PTP opening and cytochrome c release is conserved and has been studied in models of oxidative stress and calcium dysregulation. Modulators of PTP opening are therefore explored as neuroprotective strategies.
From positive regulation of mitochondrial membrane permeability involved in apoptotic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is a candidate gene required for mitochondrial permeabilization during apoptosis? | CRISPR knockout in cancer or cardiomyocyte cell lines followed by cytochrome c release assays |
| Does a specific phosphorylation site regulate PTP opening? | Point-mutation knock-in of phospho-dead or phospho-mimetic residues |
| Does a disease-associated variant alter apoptosis sensitivity? | Knock-in of the patient variant using CRISPR homology-directed repair |
| Where and when is a regulator expressed during apoptosis? | Endogenous tagged knock-in with fluorescent or epitope tags |
| Does overexpression of an anti-apoptotic gene block permeabilization? | Doxycycline-inducible overexpression in cell lines |
| Which genes modulate PTP opening in a genome-wide manner? | CRISPR library screening with apoptosis or mitochondrial permeability readouts |
How to Study the positive regulation of mitochondrial membrane permeability involved in apoptotic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Calcein-AM/CoCl2 assay | PTP opening | Live-cell imaging of mitochondrial permeability transition |
| TMRM staining | Mitochondrial membrane potential | Flow cytometry or microscopy after apoptotic stimuli |
| Cytochrome c release assay | MOMP | Subcellular fractionation and western blot |
| CRISPR knockout screening | Gene requirement for permeabilization | Genome-wide screens with apoptosis reporters |
| Phosphoproteomics | Signaling changes regulating PTP | Kinase pathway analysis in cancer cells |
| Proximity labeling | Protein interactions at mitochondria | Mapping PTP and BCL-2 family interactomes |
| Live-cell confocal imaging | Kinetics of permeabilization | Time-lapse after drug treatment |
| Mitochondrial swelling assay | PTP-dependent swelling | Isolated mitochondria treated with calcium |
Live-cell imaging of mitochondrial permeability
Fluorescent dyes such as calcein-AM or tetramethylrhodamine methyl ester (TMRM) can monitor mitochondrial membrane potential and PTP opening in live cells. Time-lapse imaging after apoptotic stimuli reveals the kinetics of permeabilization and cytochrome c release.
Cytochrome c release assays
Subcellular fractionation followed by western blotting for cytochrome c in cytosolic and mitochondrial fractions is a classic method to quantify mitochondrial outer membrane permeabilization. Immunofluorescence can also visualize cytochrome c redistribution.
CRISPR-based functional genomics
Genome-wide CRISPR knockout or activation screens coupled with apoptosis or mitochondrial permeability reporters can identify positive and negative regulators of GO:1902110. Hits are validated with individual knockouts and rescue experiments.
Proteomics and interactomics
Affinity purification or proximity labeling of PTP components and BCL-2 family proteins can reveal dynamic interactions during apoptosis. Phosphoproteomics identifies signaling events that regulate pore opening.
How CRISPR Can Be Used to Study GO:1902110 positive regulation of mitochondrial membrane permeability involved in apoptotic process
Knockout
CRISPR knockout of candidate genes such as BAX, BAK, or PPIF is used to test whether they are required for mitochondrial permeabilization during apoptosis. For example, PPIF knockout cells are resistant to calcium-induced PTP opening, and BAX/BAK double knockout cells fail to release cytochrome c.
Point Mutation
Point mutations can be introduced to test the role of specific phosphorylation sites or disease-associated variants in regulators such as GSK3B or BCL2. Phospho-dead or phospho-mimetic knock-in models reveal how post-translational modifications tune PTP opening.
Knock-in
Knock-in of fluorescent tags (e.g., GFP) or epitope tags into endogenous loci allows real-time tracking of proteins like cytochrome c or BAX during permeabilization. Disease-variant knock-in models can assess how mutations alter apoptosis sensitivity.
Overexpression
Doxycycline-inducible overexpression of anti-apoptotic genes such as BCL2 or BCL2L1 is used to test whether they block mitochondrial permeabilization and confer chemoresistance. Conversely, overexpression of pro-apoptotic BAX can sensitize cells to death.
How EDITGENE Supports positive regulation of mitochondrial membrane permeability involved in apoptotic process Research
Researchers studying positive regulation of mitochondrial membrane permeability involved in apoptotic process-related genes often need to determine whether a candidate gene is causally involved in pore opening, cytochrome c release, or apoptosis sensitivity. EDITGENE provides a comprehensive suite of CRISPR cell model services to enable these functional studies with high precision and reproducibility.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of mitochondrial membrane permeability involved in apoptotic process research.
Frequently Asked Questions About positive regulation of mitochondrial membrane permeability involved in apoptotic process
What is GO:1902110?
GO:1902110 is a Gene Ontology biological process term for any positive regulation of mitochondrial membrane permeability that is involved in apoptotic process, including PTP opening and MOMP.
What genes are involved in positive regulation of mitochondrial membrane permeability involved in apoptotic process?
Key genes include BAX, BAK, BCL2, BCL2L1, PPIF, VDAC1, GSK3B, and PIK3CA, among others.
How is mitochondrial membrane permeability measured?
Common methods include calcein-AM/CoCl2 assays, TMRM staining, cytochrome c release assays, and mitochondrial swelling assays.
What is the difference between MOMP and MPT?
MOMP refers to outer membrane permeabilization often mediated by BAX/BAK, while MPT refers to opening of the inner membrane permeability transition pore, though both increase mitochondrial permeability during apoptosis.
Which diseases are linked to mitochondrial membrane permeabilization?
Cancer chemoresistance, ischemia-reperfusion injury, cardiomyocyte death, and neurodegeneration are linked to dysregulated mitochondrial permeabilization.
Can CRISPR be used to study mitochondrial permeability?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are widely used to dissect gene function in this process.
What is the role of GSK-3beta in PTP opening?
Inhibition of PI3K/Akt/GSK-3beta signaling facilitates PTP opening in hepatocellular carcinoma cells.
How does sanguinarine affect mitochondrial permeabilization?
Sanguinarine triggers intrinsic apoptosis in colorectal cancer through dissociation of STRAP and MELK, leading to mitochondrial permeabilization.
What is the role of TRIM25 in mitochondrial DNA release?
TRIM25 triggers pyroptosis through mitochondrial DNA release in intestinal ischemia-reperfusion injury.
How does NRIP1 affect cardiomyocyte mitochondria?
NRIP1, downstream of YY1, promotes OGD/R-induced mitochondrial dysfunction in H9c2 cardiomyocytes.
Conclusion
GO:1902110 captures the critical apoptotic process of increasing mitochondrial membrane permeability, a decisive step in intrinsic cell death. Its regulation by BCL-2 family proteins, kinases, and PTP components makes it a central node in cancer, cardiovascular, and inflammatory diseases. CRISPR-based cell models are indispensable for causally linking specific genes to this process and for identifying new therapeutic targets.
References
- 1. Fedotcheva T et al.. 2022. Involvement of Multidrug Resistance Modulators in the Regulation of the Mitochondrial Permeability Transition Pore.. Membranes (Basel) 12(9) PMID: 36135908
- 2. Song Y et al.. 2026. TRIM25 triggers pyroptosis through mitochondrial DNA release in intestinal ischemia-reperfusion injury.. Free Radic Biol Med 247:333-347 PMID: 41679564
- 3. Ahad A et al.. 2026. Ferroptosis-Mitochondrial Crosstalk in Cardiomyocyte Death: The Cardiomyocyte Ferroptotic Amplification Circuit (CFAC) as a Proposed, Testable Systems Framework.. Cardiovasc Toxicol 26(10) PMID: 42726159
- 6. Zhang W et al.. 2025. NRIP1 is a downstream target of YY1 in promoting OGD/R-induced H9c2 cardiomyocyte injury and mitochondrial dysfunction.. Histol Histopathol 40(5):773-784 PMID: 39422202
- 7. Zhou LJ et al.. 2018. Erinacine Facilitates the Opening of the Mitochondrial Permeability Transition Pore Through the Inhibition of the PI3K/ Akt/GSK-3β Signaling Pathway in Human Hepatocellular Carcinoma.. Cell Physiol Biochem 50(3):851-867 PMID: 30355923
- 8. Gong X et al.. 2018. Sanguinarine triggers intrinsic apoptosis to suppress colorectal cancer growth through disassociation between STRAP and MELK.. BMC Cancer 18(1):578 PMID: 29783958
