Protection from inactivation of the adenine nucleotide translocator during hypoglycaemia-induced apoptosis by mitochondrial phospholipid hydroperoxide glutathione peroxidase
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We demonstrated that mitochondrial phospholipid hydroperoxide glutathione peroxidase (PHGPx) first suppressed the dissociation of cytochrome c (cyt c) from cardiolipin (CL) in mitochondrial inner membranes and then apoptosis caused by the hypoglycaemia by the prevention of peroxidation of CL [Nomura, Imai, Koumura, Arai and Nakagawa (1999) J. Biol. Chem. 274, 29294–29302; Nomura, Imai, Koumura, Kobayashi and Nakagawa (2000) Biochem. J. 351, 183–193]. The present study shows the involvement of peroxidation of CL in the inactivation of adenine nucleotide translocator (ANT) and the opening of permeability transition pores by using the system of ANT-reconstituted liposome and isolated mitochondria. ANT activity appeared in dioleoyl phosphatidylcholine proteoliposome containing 10% (mol/mol) CL or phosphatidylglycerol (PG), but not other classes of phospholipids. ANT activity was competitively inhibited by the addition of cardiolipin hydroperoxide (CLOOH) in reconstituted liposomes containing CL. However, phosphatidylcholine hydroperoxide failed to inactivate the activity of ANT. The activity of ANT in reconstituted liposomes, including CLOOH, recovered when CLOOH in reconstituted liposome was reduced to hydroxycardiolipin by incubation with PHGPx. The activity of ANT was determined in rat basophil leukaemia RBL2H3 cells after their exposure to 2-deoxyglucose. ANT activity decreased to 50% of the control level by 4 h in response to apoptosis. In parallel, cyt c and apoptosis-inducing factor (AIF) were released from mitochondria. Suppression of the accumulation of CLOOH by overexpression of PHGPx in mitochondria effectively prevented the inactivation of ANT, the opening of permeability transition pores and the release of cyt c and AIF from mitochondria in hypoglycaemia-induced apoptotic cells. These findings suggest that mitochondrial PHGPx might be involved in the modulation of the activity of ANT and the opening of pores for the release of cyt c via the modulation of levels of CLOOH in the mitochondria.
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Atractyloside is an agonist of ANT and opens the MPTP.
“an agonist of ANT, atractyloside (ATR), opens the MPTP (Imai et al., 2003).”
From Mitochondrial Dysfunction Induced by Sertraline, an Antidepressant Agent (2012) · cites this paper as Imai et al., 2003
The Introduction (page unavailable) says atractyloside binds ANT but calls it a pharmacological inhibitor of ANT, not an agonist. The section on isolated mitochondria (page unavailable) says atractyloside can induce PT-pore opening, supporting the MPTP-opening part of the claim. (LLM, conf=0.90)
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- Authors
- IMAI, H., KOUMURA, T., NAKAJIMA, R., NOMURA, K., & NAKAGAWA, Y.
- Affiliations
- Kitasato University (JP)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2003-05-01
- Volume
- 371
- Issue
- 3
- Pages
- 799-809
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1223322
- OpenAlex
- W2020340280
- Cited by
- 67
- References
- 54
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 3 · 2021: 2 · 2019: 1 · 2018: 3 · 2017: 1 · 2016: 3 · 2014: 1 · 2013: 4 · 2012: 1
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Naito Foundation
- Takeda Science Foundation
- Japan Society for the Promotion of Science (10672052)
- 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
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Keywords
- adenine nucleotide translocase, cardiolipin peroxidation, cytochrome c release, apoptosis-inducing factor, inner mitochondrial membrane, 2-deoxyglucose
- MeSH terms
- Phospholipid Hydroperoxide Glutathione Peroxidase, Mitochondrial ADP, ATP Translocases, Animals, Cardiolipins, Cell Line, Glutathione Peroxidase, Hypoglycemia, Liposomes, Mitochondria, Apoptosis, Rats
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