Initiation of Apoptotic Signal by the Peroxidation of Cardiolipin of Mitochondria
Abstract
A bstract: Overexpression of phospholipid hydroperoxide glutathione peroxidase (PHGPx) in mitochondria of RBL2H3 cells (M15 cells) prevented the release of cytochrome c (cyt.c), the activation of caspase‐3, and apoptosis caused by 2‐deoxyglucose (2DG), whereas cells overexpressing nonmitochondrial PHGPx(L9) and control (S1) cells were induced to apoptosis. Hydro‐peroxide levels in mitochondria of L9 and S1 cells were significantly enhanced by 2DG‐induced apoptosis. In contrast, generation of hydroperoxide in mitochondria was protected in M15 cells, which also showed resistance to apoptosis by etoposide, staurosporine, UV irradiation, cycloheximide, and actinomycin D, stimuli that induce apoptosis by the liberation of cyt.c from mitochondria. Cyt.c preferentially binds to the monolayer of cardiolipin (CL), the specific phospholipid of the inner membrane of mitochondria. The amount of cyt.c bound to the monolayer of cardiolipin hydroperoxide (CL‐OOH) was much lower than that bound to CL. Cyt.c bound to liposome containing CL was released by peroxidation with a radical initiator. Adenine nucleotide translocator (ANT), which regulates the opening and closing the permeability transition (PT) pore, potentially was inactivated in apoptosis‐induced S1 cells 4 h after the addition of 2DG, coincidentally with cyt.c release from mitochondria. ANT activity was suppressed by the fusion of isolated mitochondria with liposomes containing CL‐OOH. ANT activity was expressed in proteoliposomes containing 10% CL, but it was competitively inhibited by the addition of CL‐OOH. This study suggests that CL peroxidation might have an initiating role in the liberation of cyt.c from the inner membrane, and in the opening of the PT pore via inactivation of ANT. Mitochondrial PHGPx might play a role as an anti‐apoptotic factor by protecting CL and reducing CL‐OOH.
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Cardiolipin may be oxidized in part through the peroxidase activity of cytochrome c in response to increased production of hydrogen peroxide after disruption in electron transport.
“Interestingly, cardiolipin may be oxidized, in part, through the peroxidase activity of cytochrome c in response to increased production of hydrogen peroxide after disruption in electron transport (34, 310).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [310]
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- Authors
- NAKAGAWA, Y.
- Affiliations
- Kitasato University (JP)
- Corresponding author
- NAKAGAWA, YASUHITO
- Venue
- Annals of the New York Academy of Sciences
- Publisher
- Wiley
- Published
- 2004-04
- Volume
- 1011
- Issue
- 1
- Pages
- 177-184
- ISSN
- 0077-8923 (ISSN-L)
- 1749-6632
- OpenAlex
- W4237644036
- Cited by
- 60
- References
- 32
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 1 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 2 · 2014: 4 · 2013: 2 · 2012: 5
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of the New York Academy of Sciences (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- cardiolipin peroxidation, phospholipid hydroperoxide glutathione peroxidase, cytochrome c release, apoptosis, adenine nucleotide translocase, mitochondrial permeability transition pore, 2-deoxyglucose, caspase-3 activation, inner mitochondrial membrane, anti-apoptotic factors
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