Cited by 175Cell death mechanisms and regulationMitochondrial Function and PathologyAutophagy in Disease and Therapy

Apoptotic interactions of cytochrome c: Redox flirting with anionic phospholipids within and outside of mitochondria

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Bayir, H., Fadeel, B., Palladino, M.J., Witasp, E., Kurnikov, I.V., Tyurina, Y.Y., Tyurin, V.A., Amoscato, A.A. +6 more·2006·Biochimica et Biophysica Acta (BBA) - Bioenergetics

Abstract

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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Crossref · 10.1016/j.bbabio.2006.03.002

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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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  1. 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.
  2. 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.

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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.
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
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

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