Peroxidase Activity and Structural Transitions of Cytochrome c Bound to Cardiolipin-Containing Membranes
Open accessAbstract
During apoptosis, cytochrome c (cyt c) is released from intermembrane space of mitochondria into the cytosol where it triggers the caspase-dependent machinery. We discovered that cyt c plays another critical role in early apoptosis as a cardiolipin (CL)-specific oxygenase to produce CL hydroperoxides required for release of pro-apoptotic factors [Kagan, V. E., et al. (2005) Nat. Chem. Biol. 1, 223-232]. We quantitatively characterized the activation of peroxidase activity of cyt c by CL and hydrogen peroxide. At low ionic strength and high CL/cyt c ratios, peroxidase activity of the CL/cyt c complex was increased >50 times. This catalytic activity correlated with partial unfolding of cyt c monitored by Trp(59) fluorescence and absorbance at 695 nm (Fe-S(Met(80)) band). The peroxidase activity increase preceded the loss of protein tertiary structure. Monounsaturated tetraoleoyl-CL (TOCL) induced peroxidase activity and unfolding of cyt c more effectively than saturated tetramyristoyl-CL (TMCL). TOCL/cyt c complex was found more resistant to dissociation by high salt concentration. These findings suggest that electrostatic CL/cyt c interactions are central to the initiation of the peroxidase activity, while hydrophobic interactions are involved when cyt c's tertiary structure is lost. In the presence of CL, cyt c peroxidase activity is activated at lower H(2)O(2) concentrations than for isolated cyt c molecules. This suggests that redistribution of CL in the mitochondrial membranes combined with increased production of H(2)O(2) can switch on the peroxidase activity of cyt c and CL oxidation in mitochondria-a required step in execution of apoptosis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The heme iron of cytochrome c is predominately hexacoordinate, but can become pentacoordinate when the iron-methionine bond is ruptured which occurs when the methionine is oxidized, tyrosines are nitrated, or the cytochrome interacts with anionic phospholipids.
“Similar to Ngb, the heme iron of cytochrome c is predominately hexacoordinate, but can become pentacoordinate when the iron-methionine bond is ruptured which occurs when the methionine is oxidized [65, 66], tyrosines are nitrated [67, 68], or the cytochrome interacts with anionic phospholipids such as those present in the inner membrane of the mitochondria [69–71].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [70]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Yung-Chi, C., & Prusoff, W. H. (1973) · Biochemical Pharmacology · doi:10.1016/0006-2952(73)90196-2 · Cited by 12,922 · see citing works
Esters of Methanesulfonic Acid as Irreversible Inhibitors of Acetylcholinesterase
Kitz, R. J., & Wilson, I. B. (1962) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)50153-8 · Cited by 1,523 · see citing works
Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors
Kagan, V. E., Tyurin, V. A., Jiang, J., Tyurina, Y. Y., Ritov, V. B., Amoscato, A. A., Osipov, A. N., Belikova, N. A., Kapralov, A. A., Kini, V., et al. (2005) · Nature Chemical Biology · doi:10.1038/nchembio727 · Cited by 1,256 · see citing works
Self-citationHigh-resolution three-dimensional structure of horse heart cytochrome c
Bushnell, G. W., Louie, G. V., & Brayer, G. D. (1990) · Journal of Molecular Biology · doi:10.1016/0022-2836(90)90200-6 · Cited by 1,056 · see citing works
Cytochrome c release from mitochondria proceeds by a two-step process
Ott, M., Robertson, J. D., Gogvadze, V. G., Zhivotovsky, B., & Orrenius, S. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.241655498 · Cited by 955 · see citing works
Crystal structure of yeast cytochrome c peroxidase refined at 1.7-A resolution.
Finzel, B. C., Poulos, T. L., & Kraut, J. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)90651-4 · Cited by 714 · see citing works
The stereochemistry of peroxidase catalysis.
Poulos, T. L., & Kraut, J. (1980) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)70630-9 · Cited by 688 · see citing works
Direct Observation of the Three-State Folding of a Single Protein Molecule
Cecconi, C., Shank, E. A., Bustamante, C., & Marqusee, S. (2005) · Science · doi:10.1126/science.1116702 · Cited by 635 · see citing works
Petit, J., Maftah, A. A., Ratinaud, M., & Julien, R. (1992) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1992.tb17285.x · Cited by 334 · see citing works
Phospholipid-Cytochrome c Interaction
Tuominen, E. K. J., Wallace, C. J. A., & Kinnunen, P. K. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200056200 · Cited by 309 · see citing works
Protein folding: The stepwise assembly of foldon units
Maity, H., Maity, M., Mallela, K. M. G., Mayne, L. C., & Englander, S. W. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501043102 · Cited by 299 · see citing works
McMillin, J. B., & Dowhan, W. (2002) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/s1388-1981(02)00329-3 · Cited by 266 · see citing works
Pettigrew, G. W., & Moore, G. R. (1987) · Springer series in molecular biology · doi:10.1007/978-3-642-72698-9 · Cited by 247 · see citing works
Cytochrome c binding to enzymes and membranes
Nicholls, P. J. (1974) · Biochimica et Biophysica Acta (BBA) - Reviews on Bioenergetics · doi:10.1016/0304-4173(74)90003-2 · Cited by 242 · see citing works
Kirkland, R. A., Adibhatla, R. M., Hatcher, J. F., & Franklin, J. L. (2002) · Neuroscience · doi:10.1016/s0306-4522(02)00512-2 · Cited by 171 · see citing works
Reaction of haem containing proteins and enzymes with hydroperoxides: The radical view
Svistunenko, D. A. (2005) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2005.01.004 · Cited by 155 · see citing works
Burkitt, M. J., & Wardman, P. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.4578 · Cited by 154 · see citing works
Cytochrome c-catalyzed oxidation of organic molecules by hydrogen peroxide
Radí, R., Thomson, L., Rubbo, H., & Prodanov, E. (1991) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(91)90171-e · Cited by 148 · see citing works
Heimburg, T., & Marsh, D. (1995) · Biophysical Journal · doi:10.1016/s0006-3495(95)80215-8 · Cited by 146 · see citing works
Pinheiro, T. J. T., Elöve, G. A., Watts, A. B., & Röder, H. (1997) · Biochemistry · doi:10.1021/bi971235z · Cited by 141 · see citing works
The Point of No Return: Mitochondria, Caspases, and the Commitment to Cell Death
Green, D. R., & Amarante-Mendes, G. P. (1998) · Results and problems in cell differentiation · doi:10.1007/978-3-540-69185-3_3 · Cited by 135 · see citing works
Barr, D. P., Gunther, M. R., Deterding, L. J., Tomer, K. B., & Mason, R. P. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.26.15498 · Cited by 132 · see citing works
Cytochrome c-catalyzed membrane lipid peroxidation by hydrogen peroxide
Radí, R., Turrens, J. F., & Freeman, B. Α. (1991) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(91)90172-f · Cited by 128 · see citing works
Peroxidase Activity as a Tool for Studying the Folding of c -Type Cytochromes
Diederix, R. E. M., Ubbink, M., & Canters, G. W. (2002) · Biochemistry · doi:10.1021/bi0260841 · Cited by 114 · see citing works
Peripheral and Integral Binding of Cytochrome c to Phospholipids Vesicles
Oellerich, S., Lecomte, S., Paternostre, M., Heimburg, T., & Hildebrandt, P. (2004) · The Journal of Physical Chemistry B · doi:10.1021/jp036799t · Cited by 111 · see citing works
Protein oxidation of cytochrome c by reactive halogen species enhances its peroxidase activity
Chen, Y.-R., Deterding, L. J., Sturgeon, B. E., Tomer, K. B., & Mason, R. P. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200709200 · Cited by 110 · see citing works
Direct Cardiolipin Assay in Yeast Using the Red Fluorescence Emission of 10-N-Nonyl Acridine Orange
Gallet, P., Maftah, A. A., Petit, J., et al. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.0113o.x · Cited by 99 · see citing works
Direct Cardiolipin Assay in Yeast Using the Red Fluorescence Emission of 10-N-Nonyl Acridine Orange
Gallet, P., Maftah, A. A., Petit, J., et al. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.tb20238.x · Cited by 84 · see citing works
Unfolding and refolding of cytochrome c driven by the interaction with lipid micelles
Sanghera, N., & Pinheiro, T. J. T. (2000) · Protein Science · doi:10.1110/ps.9.6.1194 · Cited by 74 · see citing works
Berezhna, S. Y., Wohlrab, H., & Champion, P. M. (2003) · Biochemistry · doi:10.1021/bi027387y · Cited by 70 · see citing works
Pinheiro, T. J. T. (1994) · Biochimie · doi:10.1016/0300-9084(94)90173-2 · Cited by 62 · see citing works
Initiation of Apoptotic Signal by the Peroxidation of Cardiolipin of Mitochondria
Nakagawa, Y. (2004) · Springer eBooks · doi:10.1007/978-3-662-41088-2_18 · Cited by 61 · see citing works
Equilibrium and kinetics of the unfolding of α-lactalbumin by guanidine hydrochloride
Sugai, S., Yashiro, H., & Nitta, K. (1973) · Biochimica et Biophysica Acta (BBA) - Protein Structure · doi:10.1016/0005-2795(73)90327-9 · Cited by 53 · see citing works
ATP specifically drives refolding of non‐native conformations of cytochrome c
Sinibaldi, F., Mei, G., Polticelli, F., Piro, M. C., Howes, B. D., Smulevich, G., Santucci, R., Ascoli, F., & Fiorucci, L. (2005) · Protein Science · doi:10.1110/ps.041069405 · Cited by 47 · see citing works
Effects of interface mutations on association modes and electron-transfer rates between proteins
Kang, S. A. W., & Crane, B. R. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505176102 · Cited by 45 · 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
Jiang, J., Kini, V., Belikova, N. A., et al. (2004) · Lipids · doi:10.1007/s11745-004-1340-1 · Cited by 39 · see citing works
Self-citationLipid specificity for membrane mediated partial unfolding of cytochrome c
de Jongh, H. H., Ritsema, T., & Killian, J. A. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)00115-p · Cited by 33 · see citing works
Kinetics and mechanism of the folding of cytochrome c
Pryse, K. M., Bruckman, T. G., Maxfield, B. W., et al. (1992) · Biochemistry · doi:10.1021/bi00137a006 · Cited by 32 · see citing works
Equilibrium and kinetics of the unfolding of α-lactalbumin by guanidine hydrochloride (II)
Kita, N., Kuwajima, K., Nitta, K., et al. (1976) · Biochimica et Biophysica Acta (BBA) - Protein Structure · doi:10.1016/0005-2795(76)90310-x · Cited by 27 · see citing works
Jori, G., Tamburro, A. M., & Azzi, A. (1974) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.1974.tb06521.x · Cited by 26 · see citing works
Haem-oxygen reactive intermediates: catalysis by the two-step
Makris, T. M., Denisov, I. G., & Sligar, S. G. (2003) · Biochemical Society Transactions · doi:10.1042/bst0310516 · Cited by 20 · see citing works
Hagihara, B., Tagawa, K., Morikawa, I., et al. (1958) · Nature · doi:10.1038/1811588a0 · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Reactive Oxygen Species in Inflammation and Tissue Injury
Mittal, M., Siddiqui, M. R., Tran, K., Reddy, S. P., & Malik, A. B. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.5149 · Cited by 4,897 · see citing works
Maia, L. B., & Moura, J. J. G. (2014) · Chemical Reviews · doi:10.1021/cr400518y · Cited by 401 · see citing works
Nitrite reductase activity of cytochrome c
Basu, S., Azarova, N. A., Font, M. D., King, S. B., Hogg, N., Gladwin, M. T., Shiva, S., & Kim-Shapiro, D. B. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806934200 · Cited by 214 · see citing works
Basova, L. V., Kurnikov, I. V., Wang, L., Ritov, V. B., Belikova, N. A., Vlasova, I. I., Pacheco, A. A., Winnica, D. E., Peterson, J., Bayir, H., et al. (2007) · Biochemistry · doi:10.1021/bi061854k · Cited by 212 · see citing works
Self-citationBayir, 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., et al. (2006) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2006.03.002 · Cited by 175 · see citing works
Self-citationMechanisms of nitrite bioactivation
Kim-Shapiro, D. B., & Gladwin, M. T. (2014) · Nitric Oxide · doi:10.1016/j.niox.2013.11.002 · Cited by 157 · see citing works
Cardiolipin Remodeling in the Heart
Sparagna, G. C., & Lesnefsky, E. J. (2009) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e31819b5461 · Cited by 128 · see citing works
Szczepanek, K., Chen, Q., Larner, A. C., & Lesnefsky, E. J. (2012) · Mitochondrion · doi:10.1016/j.mito.2011.08.011 · Cited by 117 · 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
Bueno, M., Wang, J., Mora, A. L., & Gladwin, M. T. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.4833 · Cited by 68 · see citing works
Li, M., Mandal, A., Tyurin, V. A., DeLucia, M., Ahn, J., Kagan, V. E., & van der Wel, P. C. A. (2019) · Structure · doi:10.1016/j.str.2019.02.007 · Cited by 41 · see citing works
Self-citationYanamala, N., Kapralov, A. A., Djukic, M., Peterson, J., Mao, G., Klein-Seetharaman, J., Stoyanovsky, D. A., Stursa, J., Neuzil, J., & Kagan, V. E. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.601377 · Cited by 19 · see citing works
Self-citation
- Authors
- Belikova, N. A., Vladimirov, Y. A., Osipov, A. N., Kapralov, A. A., Tyurin, V. A., Potapovich, M. V., Basova, L. V., Peterson, J., Kurnikov, I. V., & Kagan, V. E.
- Affiliations
- University of Pittsburgh (US)
- Center for Free Radical and Antioxidant Health and Department of Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Suite 350, Pittsburgh, Pennsylvania 15219-3130, Department of Medical Biophysics, Faculty of Fundamental Medicine, Moscow State Lomonosov University, 31/5 Lomonosovsky Avenue, Moscow 119192, Russia, and Department of Biophysics, Medical-Biological Faculty, Russian State Medical University, 1 Ostrovitjanova Street, Moscow 117997, Russia
- Corresponding author
- Kagan, Valerian E.
- ORCID
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2006-03-25
- Volume
- 45
- Issue
- 15
- Pages
- 4998-5009
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC2527545
- OpenAlex
- W2052401089
- Cited by
- 398
- References
- 43
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 14 · 2023: 24 · 2022: 17 · 2021: 22 · 2020: 23 · 2019: 17 · 2018: 14 · 2017: 24 · 2016: 14 · 2015: 30 · 2014: 22 · 2013: 28 · 2012: 17
- FWCI
- 7.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-61411, R01HL061411, R01HL070755)
- National Institute of Allergy and Infectious Diseases (U19AI068021)
- National Institute for Occupational Safety and Health (OH008282)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- cytochrome c, cardiolipin, peroxidase activity, apoptosis, protein unfolding, hydrogen peroxide, mitochondrial membrane, electrostatic interactions, hydrophobic interactions, caspase activation
- MeSH terms
- Acridine Orange, Animals, Binding, Competitive, Cardiolipins, Cell Membrane, Electrophoresis, Enzyme Activation, Etoposide, Fluoresceins, Horses, Lipids, Liposomes, Peroxidase, Osmolar Concentration, Oxidation-Reduction, Phosphatidylcholines, Spectrometry, Fluorescence, Structure-Activity Relationship, Time Factors, Tryptophan, Cytochromes c, Hydrophobic and Hydrophilic Interactions
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
