Mitochondrial permeability transition: molecular mechanisms & dependencies

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

Human evidence only

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

What acts on it

Cyclosporin A inhibited the large-amplitude swelling that isolated rat liver and heart mitochondria show when exposed to 250 micromolar calcium, with the number of cyclosporin-binding sites titrated at 113.7 plus or minus 5.0 and 124.3 plus or minus 11.2 picomoles per milligram of protein and a Ki of about 5 nanomolar.
Cyclosporine → Mitochondrial permeability transition source_derived_draftungraded
Experimental context and source evidence
duration
Not stated here
evidence_access
Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
experimental_model
Rat liver and heart mitochondria
exposure
Cyclosporin A, titrated
limitations
Isolated mitochondria under respiratory-chain inhibition in KSCN or sucrose medium, with 250 micromolar calcium, which is a supraphysiological calcium load in a stripped system. Bongkrekic acid inhibited swelling in both media and ADP inhibited it in KSCN medium with the effect reversed by carboxyatractyloside, so the adenine nucleotide carrier is implicated alongside the isomerase. The proposed interaction between the two is the authors' model, not a measurement.
organism
Rat liver and heart mitochondria
plain_language
Cyclosporin A inhibited the large-amplitude swelling that isolated rat liver and heart mitochondria show when exposed to 250 micromolar calcium, with the number of cyclosporin-binding sites titrated at 113.7 plus or minus 5.0 and 124.3 plus or minus 11.2 picomoles per milligram of protein and a Ki of about 5 nanomolar.
primary_references
Inhibition of Ca2+-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondrial-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. (1990). https://pubmed.ncbi.nlm.nih.gov/2160810/ DOI: 10.1042/bj2680153
route
In vitro
tissue
Calcium-induced inner-membrane pore opening
Cyclosporine: the complex that inhibits calcineurin, a second cyclophilin, and the transport step that decides exposure (2026-09-23) · lines 135–135
Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata on 2026-09-23. No reference carries a recorded retraction, erratum or expression of concern. Each of the seven is a separate laboratory and each carries its own lineage key, so none of them can be counted twice as independent support. Study-specific concentrations, kinetic constants and limitations retained. Not publisher full text. · supports · Rat liver and heart mitochondria · source_derived_draft · unverified_draft
Cyclosporin A inhibited the large-amplitude swelling that isolated rat liver and heart mitochondria show when exposed to 250 micromolar calcium, with the number of cyclosporin-binding sites titrated at 113.7 plus or minus 5.0 and 124.3 plus or minus 11.2 picomoles per milligram of protein and a Ki of about 5 nanomolar.
Complete structured claim and evidence
Calcium-overload conditions induce cyclophilin-D-sensitive mitochondrial permeability transition and swelling in the tested mouse preparations.
Calcium ion → Mitochondrial permeability transition source_derived_draftungraded
Experimental context and source evidence
compartment_description
Inner mitochondrial membrane and matrix
experimental_model
Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts
limitations
Experimental overload; not all apoptosis uses this pathway and the study does not settle the molecular identity of the pore.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Excess mitochondrial calcium can trigger membrane permeability failure.
primary_references
[ca-baines2005] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death (2005). https://pubmed.ncbi.nlm.nih.gov/15800627/ DOI: 10.1038/nature03434
research_relationship_category
exposure_response
tissue_or_cell_type
Isolated liver, heart and brain mitochondria
Calcium: mechanism-first literature curation (2026-09-17) · lines 836–847
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts · source_derived_draft · unverified_draft
### ca-overload-permeability-transition Calcium-overload conditions induce cyclophilin-D-sensitive mitochondrial permeability transition and swelling in the tested mouse preparations. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Excess mitochondrial calcium can trigger membrane permeability failure. organism: Mus musculus tissue_or_cell_type: Isolated liver, heart and brain mitochondria experimental_model: Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts limitations: Experimental overload; not all apoptosis uses this pathway and the study does not settle the molecular identity of the pore. research_relationship_category: exposure_response compartment_description: Inner mitochondrial membrane and matrix [ca-baines2005] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death (2005). https://pubmed.ncbi.nlm.nih.gov/15800627/ DOI: 10.1038/nature03434
Complete structured claim and evidence

Where it participates (unsigned role)

Leflunomide given 4 hours after a hepatotoxic dose of acetaminophen afforded significant protection from liver necrosis by serum alanine aminotransferase and histopathology at 8 and 24 hours, and the mechanism was not inhibition of cytochrome-P450-catalysed bioactivation or suppression of innate immunity but inhibition of acetaminophen-induced phosphorylation of c-Jun N-terminal protein kinase, preventing downstream Bcl-2 and Bcl-XL inactivation and protecting from mitochondrial permeabilization and cytochrome c release, while also preventing induction of inducible nitric oxide synthase and formation of peroxynitrite; protection was still obtained when given 8 hours after the dose.
c-Jun N-terminal kinase → Hepatic necrosis source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/paracetamol-research/17366662.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7c7eb70728aa75fa3ac54f70703ce08d7a540b3a2a7da7e4797f27a6b1312dbb", "start_char": 0, "end_char": 1791, "text_sha256": "7c7eb70728aa75fa3ac54f70703ce08d7a540b3a2a7da7e4797f27a6b1312dbb"}
experimental_model
Male C57BL/6 mice given a hepatotoxic dose followed by leflunomide at 4 or 8 hours
exposure
750 milligrams per kilogram acetaminophen intraperitoneally, rescued with 30 milligrams per kilogram leflunomide
limitations
A rescue given hours after the dose, which separates the injury pathway from the bioactivation step. A mouse model at a dose far above therapeutic.
nutrient_topic
Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol
organism
Mouse
plain_language
The damage is done by a signalling kinase hours later, not by the chemistry of the metabolite alone, which is why a late rescue works.
primary_references
[apap-p17366662] Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen-induced liver injury. (2007). https://pubmed.ncbi.nlm.nih.gov/17366662/ DOI: 10.1002/hep.21475
tissue_or_cell_type
Liver
trigger_kind
biomarker_context Imported condition classification; unverified.
Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 415–426
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Male C57BL/6 mice given a hepatotoxic dose followed by leflunomide at 4 or 8 hours · source_derived_draft · unverified_draft
### apap-jnk-not-bioactivation Leflunomide given 4 hours after a hepatotoxic dose of acetaminophen afforded significant protection from liver necrosis by serum alanine aminotransferase and histopathology at 8 and 24 hours, and the mechanism was not inhibition of cytochrome-P450-catalysed bioactivation or suppression of innate immunity but inhibition of acetaminophen-induced phosphorylation of c-Jun N-terminal protein kinase, preventing downstream Bcl-2 and Bcl-XL inactivation and protecting from mitochondrial permeabilization and cytochrome c release, while also preventing induction of inducible nitric oxide synthase and formation of peroxynitrite; protection was still obtained when given 8 hours after the dose. Condition category: biomarker_context nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The damage is done by a signalling kinase hours later, not by the chemistry of the metabolite alone, which is why a late rescue works. organism: Mouse tissue_or_cell_type: Liver experimental_model: Male C57BL/6 mice given a hepatotoxic dose followed by leflunomide at 4 or 8 hours limitations: A rescue given hours after the dose, which separates the injury pathway from the bioactivation step. A mouse model at a dose far above therapeutic. exposure: 750 milligrams per kilogram acetaminophen intraperitoneally, rescued with 30 milligrams per kilogram leflunomide evidence_span: {"source_cache": "artifacts/paracetamol-research/17366662.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7c7eb70728aa75fa3ac54f70703ce08d7a540b3a2a7da7e4797f27a6b1312dbb", "start_char": 0, "end_char": 1791, "text_sha256": "7c7eb70728aa75fa3ac54f70703ce08d7a540b3a2a7da7e4797f27a6b1312dbb"} [apap-p17366662] Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen-induced liver injury. (2007). https://pubmed.ncbi.nlm.nih.gov/17366662/ DOI: 10.1002/hep.21475
Complete structured claim and evidence

The events it takes part in

A mechanism often involves more than two components. These are the full events, with every participant and its role.

Situations it appears in

Low-supply and faulty-machinery situations recorded in the chapters where this component plays a part.

In the sources

Preserved passages that mention this component, quoted exactly. Open one to read it in context.

Open hypotheses

Proposed ideas that involve this component. They are labeled as hypotheses and do not change any recorded statement.

This is a research prototype built from draft material. It is not medical advice, and its statements still await verification against the original studies.

Mitochondrial permeability transition