Opening of the Mitochondrial Permeability Transition Pore Induces Reactive Oxygen Species Production at the Level of the Respiratory Chain Complex I
Open accessAbstract
We have investigated the consequences of permeability transition pore (PTP) opening on the rate of production of reactive oxygen species in isolated rat liver mitochondria. We found that PTP opening fully inhibited H(2)O(2) production when mitochondria were energized both with complex I or II substrates. Because PTP opening led to mitochondrial pyridine nucleotide depletion, H(2)O(2) production was measured again in the presence of various amounts of NADH. PTP opening-induced H(2)O(2) production began when NADH concentration was higher than 50 microm and reached a maximum at over 300 microm. At such concentrations of NADH, the maximal H(2)O(2) production was 4-fold higher than that observed when mitochondria were permeabilized with the channel-forming antibiotic alamethicin, indicating that the PTP opening-induced H(2)O(2) production was not due to antioxidant depletion. Moreover, PTP opening decreased rotenone-sensitive NADH ubiquinone reductase activity, whereas it did not affect the NADH FeCN reductase activity. We conclude that PTP opening induces a specific conformational change of complex I that (i) dramatically increases H(2)O(2) production so long as electrons are provided to complex I, and (ii) inhibits the physiological pathway of electrons inside complex I. These data allowed the identification of a novel consequence of permeability transition that may partly account for the mechanism by which PTP opening induces cell death.
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Loss of membrane potential may increase ROS production.
“In turn, the loss of membrane potential may increase ROS production (4).”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [4]
The Abstract (page unavailable) reports that PTP opening, which uncouples mitochondria, increased H₂O₂ production when NADH was supplied. It also reports that PTP opening inhibited H₂O₂ production without that supply, while uncoupling has been shown to decrease ROS. The paper attributes the increase to a change in complex I, not to loss of membrane potential itself. (LLM, conf=0.85)
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References 55 · Cited by 264
- Authors
- Batandier, C., Leverve, X., & Fontaine, E.
- Affiliations
- Inserm (FR)
- Corresponding author
- Fontaine, Eric
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-04
- Volume
- 279
- Issue
- 17
- Pages
- 17197-17204
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1970326476
- Cited by
- 264
- References
- 55
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 8 · 2023: 12 · 2022: 13 · 2021: 14 · 2020: 9 · 2019: 11 · 2018: 19 · 2017: 15 · 2016: 11 · 2015: 16 · 2014: 8 · 2013: 12 · 2012: 10
- FWCI
- 5.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Association pour la Recherche sur le Cancer
- Institut National de la Santé et de la Recherche Médicale
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- mitochondrial permeability transition pore, reactive oxygen species, hydrogen peroxide production, respiratory chain complex I, NADH oxidation, NADH-ubiquinone reductase, alamethicin, rat liver mitochondria, cell death mechanisms
- MeSH terms
- Mitochondrial Permeability Transition Pore, Animals, Dose-Response Relationship, Drug, Electrons, Hydrogen Peroxide, Intracellular Membranes, Ion Channels, Mitochondria, Mitochondria, Liver, Models, Chemical, NAD, Oxygen, Oxygen Consumption, Permeability, Protein Conformation, Pyridines, Rotenone, Time Factors, Cell Death, Reactive Oxygen Species, Mitochondrial Membrane Transport Proteins, Electron Transport Complex I, Rats
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