Apoptotic interactions of cytochrome c: Redox flirting with anionic phospholipids within and outside of mitochondria
Open accessAbstract
Since the (re)discovery of cytochrome c (cyt c) in the early 1920s and subsequent detailed characterization of its structure and function in mitochondrial electron transport, it took over 70 years to realize that cyt c plays a different, not less universal role in programmed cell death, apoptosis, by interacting with several proteins and forming apoptosomes. Recently, two additional essential functions of cyt c in apoptosis have been discovered that are carried out via its interactions with anionic phospholipids: a mitochondria specific phospholipid, cardiolipin (CL), and plasma membrane phosphatidylserine (PS). Execution of apoptotic program in cells is accompanied by substantial and early mitochondrial production of reactive oxygen species (ROS). Because antioxidant enhancements protect cells against apoptosis, ROS production was viewed not as a meaningless side effect of mitochondrial disintegration but rather playing some - as yet unidentified - role in apoptosis. This conundrum has been resolved by establishing that mitochondria contain a pool of cyt c, which interacts with CL and acts as a CL oxygenase. The oxygenase is activated during apoptosis, utilizes generated ROS and causes selective oxidation of CL. The oxidized CL is required for the release of pro-apoptotic factors from mitochondria into the cytosol. This redox mechanism of cyt c is realized earlier than its other well-recognized functions in the formation of apoptosomes and caspase activation. In the cytosol, released cyt c interacts with another anionic phospholipid, PS, and catalyzes its oxidation in a similar oxygenase reaction. Peroxidized PS facilitates its externalization essential for the recognition and clearance of apoptotic cells by macrophages. Redox catalysis of plasma membrane PS oxidation constitutes an important redox-dependent function of cyt c in apoptosis and phagocytosis. Thus, cyt c acts as an anionic phospholipid specific oxygenase activated and required for the execution of essential stages of apoptosis. This review is focused on newly discovered redox mechanisms of complexes of cyt c with anionic phospholipids and their role in apoptotic pathways in health and disease.
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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 [34]
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Protein oxidation of cytochrome c by reactive halogen species enhances its peroxidase activity
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Bcl-2 Family Gene Products in Cerebral Ischemia and Traumatic Brain Injury
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Self-citationRegulation of cytoplasmic stress granules by apoptosis-inducing factor
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Intrathecal Expression of Proteins Regulating Apoptosis in Acute Stroke
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Differing roles of mitochondrial nitric oxide synthase in cardiomyocytes and urothelial cells
Kanai, A., Epperly, M. W., Pearce, L. L., Birder, L. A., Zeidel, M. L., Meyers, S., Greenberger, J. S., de Groat, W., Apodaca, G. L., & Peterson, J. (2004) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00737.2003 · Cited by 73 · see citing works
Self-citationCarboxymethylation of horse heart ferricytochrome c and cyanferricytochrome c
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Role of cardiolipin on tBid and tBid/Bax synergistic effects on yeast mitochondria
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Liang, Q., Smith, A. D., Pan, S., Tyurin, V. A., Kagan, V. E., Hastings, T. G., & Schor, N. F. (2005) · Biochemical Pharmacology · doi:10.1016/j.bcp.2005.04.011 · Cited by 65 · see citing works
Self-citationAdaptor Protein Shc Is an Isoform-specific Direct Activator of the Tyrosine Kinase c-Src
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Initiation of Apoptotic Signal by the Peroxidation of Cardiolipin of Mitochondria
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Apoptosis and macrophage clearance of neutrophils: regulation by reactive oxygen species
Fadeel, B., & Kagan, V. E. (2003) · Redox Report · doi:10.1179/135100003225001511 · Cited by 61 · see citing works
Self-citationFleming, C., Maldjian, A., da Costa, D., Rullay, A. K., Haddleton, D., John, J. S. S., Penny, P., Noble, R., Cameron, N., & Davis, B. (2005) · Nature Chemical Biology · doi:10.1038/nchembio730 · Cited by 61 · see citing works
Initiation of Apoptotic Signal by the Peroxidation of Cardiolipin of Mitochondria
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Oellerich, S., Wackerbarth, H., & Hildebrandt, P. (2003) · European Biophysics Journal · doi:10.1007/s00249-003-0306-y · Cited by 51 · see citing works
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Tales of Cannibalism, Suicide, and Murder: Programmed Cell Death in C. elegans
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Pearce, L. L., Kanai, A., Epperly, M. W., & Peterson, J. (2005) · Nitric Oxide · doi:10.1016/j.niox.2005.07.010 · Cited by 47 · see citing works
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Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Alters Mitochondrial Membrane Lipids
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The presence of oxidized phosphatidylserine on Fas-mediated apoptotic cell surface
Matsura, T., Togawa, A., Kai, M., Nishida, T., Nakada, J., Ishibe, Y., Kojo, S., Yamamoto, Y., & Yamada, K. (2005) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2005.08.011 · Cited by 42 · see citing works
Prasad, S., Maiti, N. C., Mazumdar, S., et al. (2002) · Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology · doi:10.1016/s0167-4838(02)00205-4 · Cited by 42 · see citing works
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Tempol Reduces the Activation of Nuclear Factor-κB in Acute Inflammation
Cuzzocrea, S., Pisano, B., Dugo, L., et al. (2004) · Free Radical Research · doi:10.1080/10715760410001710829 · Cited by 42 · see citing works
Tyurina, Y. Y., Kawai, K., Tyurin, V. A., Liu, S., Kagan, V. E., & Fabisiak, J. P. (2004) · Antioxidants and Redox Signaling · doi:10.1089/152308604322899288 · Cited by 41 · see citing works
Self-citationAutoimmunity and apoptosis: refusing to go quietly
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Early Antioxidant Therapy with Tempol during Hemorrhagic Shock Increases Survival in Rats
Kentner, R., Safar, P. J., Behringer, W., Wu, X., Kagan, V. E., Tyurina, Y. Y., Henchir, J. J., Ma, L., Hsia, C. J. C., & Tisherman, S. A. (2002) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/00005373-200211000-00025 · Cited by 34 · see citing works
Self-citationMonoepoxide Production from Linoleic Acid by Cytochrome c in the Presence of Cardiolipin
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Vay, D., Rigamonti, C., Vidali, M., et al. (2005) · Journal of Hepatology · doi:10.1016/j.jhep.2005.06.010 · Cited by 26 · see citing works
TEMPONE reduces renal dysfunction and injury mediated by oxidative stress of the rat kidney
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PS externalization: from corpse clearance to drug delivery
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Self-citationWeinberg, A., Nylander, K. D., Yan, C., et al. (2004) · Brain Research · doi:10.1016/j.brainres.2004.03.048 · Cited by 16 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- N.V. Konduru, Y.Y. Tyurina, A.A. Shvedova, A. Starr, H. Bayir, V.E. Kagan, Phosphatidylserine functionalization of single walled carbon nanotubes confers a recognition signal for macrophages, 1st International Conference on Nanotoxicology: Biomedical Aspects, Miami, Florida, January 29-February 1, 2006.
- C.J. Binder, P.X. Shaw, M.K. Chang, A. Boullier, K. Hartvigsen, S. Hörkkö, Y.I. Miller, D.A. Woelkers, M. Corr, J.L. Witztum, The role of natural antibodies in atherogenesis, J. Lipid Res. 46 (2005) 1353-1363.
Cited by
Sorted by citations
Redox regulation of cell survival
Trachootham, D., Lu, W., Ogasawara, M. A., Valle, N. R.-D., & Huang, P. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.1957 · Cited by 1,781 · see citing works
Redox regulation of mitochondrial function
Handy, D. E., & Loscalzo, J. (2012) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.4123 · Cited by 588 · see citing works
Haendeler, J., Dröse, S., Büchner, N., Jakob, S., Altschmied, J., Goy, C., Spyridopoulos, I., Zeiher, A. M., Brandt, U., & Dimmeler, S. (2009) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.185546 · Cited by 375 · see citing works
Structural transformations of cytochrome c upon interaction with cardiolipin
Muenzner, J., & Pletneva, E. V. (2014) · Chemistry and Physics of Lipids · doi:10.1016/j.chemphyslip.2013.11.002 · Cited by 74 · see citing works
Degradation of phospholipids by oxidative stress—Exceptional significance of cardiolipin
Wiswedel, I., Gardemann, A., Storch, A., Peter, D., & Schild, L. (2010) · Free Radical Research · doi:10.3109/10715760903352841 · Cited by 69 · see citing works
- Authors
- Bayir, H., Fadeel, B., Palladino, M. J., Witasp, E., Kurnikov, I. V., Tyurina, Y. Y., Tyurin, V. A., Amoscato, A. A., Jiang, J., Kochanek, P. M., DeKosky, S. T., Greenberger, J. S., Shvedova, A. A., & Kagan, V. E.
- Affiliations
- Karolinska Institutet (SE)
- University of Pittsburgh (US)
- National Institute for Occupational Safety and Health (US)
- Corresponding author
- Kagan, V.E.
- ORCID
- Venue
- Biochimica et Biophysica Acta (BBA) - Bioenergetics
- Publisher
- Elsevier BV
- Published
- 2006-05
- Volume
- 1757
- Issue
- 5-6
- Pages
- 648-659
- ISSN
- 0005-2728 (ISSN-L)
- OpenAlex
- W2022108138
- Cited by
- 175
- References
- 150
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 6 · 2019: 8 · 2018: 9 · 2017: 3 · 2016: 6 · 2015: 8 · 2014: 13 · 2013: 12 · 2012: 13
- FWCI
- 1.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Bioenergetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pennsylvania Department of Health (SAP 4100027294)
- Vetenskapsrådet
- National Institutes of Health (NIOSH OH008282, OH008282, U19 AIO68021)
- U.S. Public Health Service (U19AIO68021)
- National Heart, Lung, and Blood Institute (HL-70755, R01HL070755)
- National Institute for Occupational Safety and Health (OH008282)
- Medical Research and Materiel Command
- Telemedicine and Advanced Technology Research Center
- 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
- cytochrome c, apoptosis, cardiolipin, phosphatidylserine, redox catalysis, oxygenase activity, reactive oxygen species, mitochondrial membrane permeabilization, caspase activation, efferocytosis, macrophage phagocytosis, anionic phospholipids
- MeSH terms
- Amino Acid Sequence, Animals, Antioxidants, Cardiolipins, Cell Membrane, Electron Transport, Humans, Mitochondria, Molecular Sequence Data, Oxidation-Reduction, Oxygenases, Peroxidases, Phospholipids, Apoptosis, Reactive Oxygen Species, Cytochromes c, Atherosclerosis, Mitochondrial Membranes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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