Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death
Abstract
Mitochondria play a critical role in mediating both apoptotic and necrotic cell death. The mitochondrial permeability transition (mPT) leads to mitochondrial swelling, outer membrane rupture and the release of apoptotic mediators. The mPT pore is thought to consist of the adenine nucleotide translocator, a voltage-dependent anion channel, and cyclophilin D (the Ppif gene product), a prolyl isomerase located within the mitochondrial matrix. Here we generated mice lacking Ppif and mice overexpressing cyclophilin D in the heart. Ppif null mice are protected from ischaemia/reperfusion-induced cell death in vivo, whereas cyclophilin D-overexpressing mice show mitochondrial swelling and spontaneous cell death. Mitochondria isolated from the livers, hearts and brains of Ppif null mice are resistant to mitochondrial swelling and permeability transition in vitro. Moreover, primary hepatocytes and fibroblasts isolated from Ppif null mice are largely protected from Ca2+-overload and oxidative stress-induced cell death. However, Bcl-2 family member-induced cell death does not depend on cyclophilin D, and Ppif null fibroblasts are not protected from staurosporine or tumour-necrosis factor-alpha-induced death. Thus, cyclophilin D and the mitochondrial permeability transition are required for mediating Ca2+- and oxidative damage-induced cell death, but not Bcl-2 family member-regulated death.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
To date, PPIF (CYPD) is the only protein whose in vivo requirement for MPT induction has been formally validated with robust genetic tools.
“To date, peptidylprolyl isomerase F (PPIF; best known as cyclophilin D, CYPD) is the only protein whose in vivo requirement for MPT induction has been formally validated with robust genetic tools (although there is consensus around the notion that CYPD does not constitute the pore-forming unit of the PTPC) [376–379].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [376]
There is consensus that CYPD does not constitute the pore-forming unit of PTPC.
“although there is consensus around the notion that CYPD does not constitute the pore-forming unit of the PTPC) [376–379].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [376]
At very high levels of Ca2+, cyclophilin D-deficient cells or cells treated with cyclosporin A still have an MPT response.
“Interestingly, at very high levels of Ca2+, cyclophilin D-deficient cells or cells treated with cyclosporin A still have an MPT response (25, 31, 167, 309).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [25]
In the absence of cyclophilin D, mice are more protected from cardiac damage after ischemia/reperfusion.
“In addition, in the absence of cyclophilin D, mice are more protected from cardiac damage after ischemia/reperfusion (25, 309);”
From Redox regulation of mitochondrial function (2012) · cites this paper as [25]
Cites
Shimizu, S., Narita, M., Tsujimoto, Y., & Tsujimoto, Y. (1999) · Nature · doi:10.1038/20959 · Cited by 2,178 · see citing works
Bossy‐Wetzel, E., Newmeyer, D. D., & Green, D. R. (1998) · The EMBO Journal · doi:10.1093/emboj/17.1.37 · Cited by 1,225 · see citing works
Bax and Adenine Nucleotide Translocator Cooperate in the Mitochondrial Control of Apoptosis
Marzo, I., Brenner, C., Zamzami, N., Jürgensmeier, J. M., Susin, S. A., Vieira, H. L. A., Prévost, M.-C., Xie, Z., Matsuyama, S., Reed, J. C., et al. (1998) · Science · doi:10.1126/science.281.5385.2027 · Cited by 1,168 · see citing works
The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore
Kokoszka, J. E., Waymire, K. G., Levy, S. E., Sligh, J. E., Cai, J., Jones, D. P., MacGregor, G. R., & Wallace, D. C. (2004) · Nature · doi:10.1038/nature02229 · Cited by 1,086 · see citing works
A Distinct Pathway Remodels Mitochondrial Cristae and Mobilizes Cytochrome c during Apoptosis
Scorrano, L., Ashiya, M., Buttle, K., Weiler, S., Oakes, S. A., Mannella, C. A., & Korsmeyer, S. J. (2002) · Developmental Cell · doi:10.1016/s1534-5807(01)00116-2 · Cited by 1,072 · see citing works
Narita, M., Shimizu, S., Ito, T., Chittenden, T., Lutz, R. J., Matsuda, H., & Tsujimoto, Y. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.14681 · Cited by 933 · see citing works
Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion
Griffiths, E. J., & Halestrap, A. P. (1995) · Biochemical Journal · doi:10.1042/bj3070093 · Cited by 838 · see citing works
The permeability transition pore complex: another view
Halestrap, A. P., McStay, G. P., & Clarke, S. J. (2002) · Biochimie · doi:10.1016/s0300-9084(02)01375-5 · Cited by 709 · see citing works
Eskes, R., Antonsson, B., Osen-Sand, A., Montessuit, S., Richter, C., Sadoul, R., Mazzei, G., Nichols, A., & Martinou, J.-C. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.143.1.217 · Cited by 651 · see citing works
Protection by Cyclosporin A of Ischemia/Reperfusion-Induced Damage in Isolated Rat Hearts
Griffiths, E. J., & Halestrap, A. P. (1993) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.1993.1162 · Cited by 587 · see citing works
Pastorino, J. G., Chen, S.-T., Tafani, M., Snyder, J. W., & Farber, J. L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.13.7770 · Cited by 578 · see citing works
The Mitochondrial Permeability Transition, Release of Cytochrome c and Cell Death
Petronilli, V., Penzo, D., Scorrano, L., Bernardi, P., & Di Lisa, F. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010604200 · Cited by 472 · see citing works
He, L., & Lemasters, J. J. (2002) · FEBS Letters · doi:10.1016/s0014-5793(01)03314-2 · Cited by 435 · see citing works
Nieminen, A. L., Saylor, A. K., Tesfai, S. A., Herman, B. A., & Lemasters, J. J. (1995) · Biochemical Journal · doi:10.1042/bj3070099 · Cited by 381 · see citing works
Clarke, S. J., McStay, G. P., & Halestrap, A. P. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202191200 · Cited by 376 · see citing works
Mitochondrial permeability transition in pH-dependent reperfusion injury to rat hepatocytes
Qian, T., Nieminen, A., Herman, B. A., & Lemasters, J. J. (1997) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1997.273.6.c1783 · Cited by 258 · see citing works
Preservation of Mitochondrial Structure and Function after Bid- or Bax-Mediated Cytochrome c Release
von Ahsen, O., Renken, C. W., Perkins, G. A., Kluck, R. M., Bossy‐Wetzel, E., & Newmeyer, D. D. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.150.5.1027 · Cited by 244 · see citing works
Isolation and Subfractionation of Mitochondria from Animal Cells and Tissue Culture Lines
Pallotti, F., & Lenaz, G. (2007) · Methods in cell biology · doi:10.1016/s0091-679x(06)80001-4 · Cited by 232 · see citing works
Kaiser, R. A., Bueno, O. F., Lips, D. J., Doevendans, P. A., Jones, F. S., Kimball, T. F., & Molkentin, J. D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313717200 · Cited by 231 · see citing works
Self-citationImberti, R., Nieminen, A. L., Herman, B. A., & Lemasters, J. J. (1993) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)38135-8 · Cited by 219 · see citing works
Mitochondrial Targeted Cyclophilin D Protects Cells from Cell Death by Peptidyl Prolyl Isomerization
Lin, D.-T., & Lechleiter, J. D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112035200 · Cited by 181 · see citing works
Bid acts on the permeability transition pore complex to induce apoptosis
Zamzami, N., Hamel, C. E., Maisse, C., Brenner, C., Muñoz-Pinedo, C., Belzacq, A.-S., Costantini, P., Vieira, H., Loeffler, M., Molle, G., et al. (2000) · Oncogene · doi:10.1038/sj.onc.1204030 · Cited by 178 · see citing works
Li, Y., Johnson, N., Capano, M., Edwards, M., & Crompton, M. (2004) · Biochemical Journal · doi:10.1042/bj20040669 · Cited by 162 · see citing works
Dual role for the ADP/ATP translocator?
Halestrap, A. P. (2004) · Nature · doi:10.1038/nature02816 · Cited by 121 · see citing works
Adams, J. W., Pagel, A. L., Means, C. K., Oksenberg, D., Armstrong, R. C., & Brown, J. H. (2000) · Circulation Research · doi:10.1161/01.res.87.12.1180 · Cited by 109 · see citing works
Chapter 1 Isolation and subfractionation of mitochondria from animal cells and tissue culture lines
Pallotti, F., & Lenaz, G. (2001) · Methods in cell biology · doi:10.1016/s0091-679x(01)65002-7 · Cited by 96 · see citing works
A binary adenoviral vector system for expressing high levels of the proapoptotic gene bax
Kagawa, S., Pearson, S. A., Ji, L., Xu, K., McDonnell, T. J., Swisher, S. G., Roth, J. A., & Fang, B. (2000) · Gene Therapy · doi:10.1038/sj.gt.3301048 · Cited by 84 · see citing works
On the Involvement of Mitochondrial Intermembrane Junctional Complexes in Apoptosis
Crompton, M. (2003) · Current Medicinal Chemistry · doi:10.2174/0929867033457197 · Cited by 77 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Self-citationMitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release
Zorov, D. B., Juhaszova, M., & Sollott, S. J. (2014) · Physiological Reviews · doi:10.1152/physrev.00026.2013 · Cited by 5,383 · see citing works
Control of inositol 1,4,5-trisphosphate-induced Ca2+ release by cytosolic Ca2+
Bootman, M. D., Missiaen, L., Parys, J. B., SMEDT, H. D., & Casteels, R. (1995) · Biochemical Journal · doi:10.1042/bj3060445 · Cited by 5,120 · see citing works
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
Yellon, D. M., & Hausenloy, D. J. (2007) · New England Journal of Medicine · doi:10.1056/nejmra071667 · Cited by 3,797 · see citing works
Mitochondrial membrane permeabilization in cell death
Kroemer, G., Galluzzi, L., & Brenner, C. (2007) · Physiological Reviews · doi:10.1152/physrev.00013.2006 · Cited by 3,598 · see citing works
Reactive oxygen species, cellular redox systems, and apoptosis
Circu, M. L., & Aw, T. Y. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.12.022 · Cited by 3,340 · see citing works
Mitochondria and cell death: outer membrane permeabilization and beyond
Tait, S. W. G., & Green, D. R. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2952 · Cited by 2,593 · see citing works
Laflamme, M. A., Chen, K. Y., Naumova, A. V., Muskheli, V., Fugate, J. A., Dupras, S. K., Reinecke, H., Xu, C., Hassanipour, M., Police, S., et al. (2007) · Nature Biotechnology · doi:10.1038/nbt1327 · Cited by 2,207 · see citing works
Cell Biology of Ischemia/Reperfusion Injury
Kalogeris, T. J., Baines, C. P., Krenz, M., & Korthuis, R. J. (2012) · International review of cytology · doi:10.1016/b978-0-12-394309-5.00006-7 · Cited by 2,202 · see citing works
Self-citationThe Role of Mitochondria in Apoptosis
Wang, C., & Youle, R. J. (2009) · Annual Review of Genetics · doi:10.1146/annurev-genet-102108-134850 · Cited by 1,987 · see citing works
Regulated necrosis: the expanding network of non-apoptotic cell death pathways
Berghe, T. V., Linkermann, A., Jouan-Lanhouet, S., Walczak, H., & Vandenabeele, P. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3737 · Cited by 1,735 · see citing works
Mitochondria as sensors and regulators of calcium signalling
Rizzuto, R., De Stefani, D., Raffaello, A., & Mammucari, C. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3412 · Cited by 1,781 · see citing works
Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel?
Sabharwal, S. S., & Schumacker, P. T. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3803 · Cited by 1,643 · see citing works
Mechanisms Underlying Acute Protection From Cardiac Ischemia-Reperfusion Injury
Murphy, E., & Steenbergen, C. (2008) · Physiological Reviews · doi:10.1152/physrev.00024.2007 · Cited by 1,472 · see citing works
A network-based analysis of systemic inflammation in humans
Program, I. A. H. R. T. I. L. S. C. R., Calvano, S. E., Xiao, W., Richards, D. R., Felciano, R. M., Baker, H. V., Cho, R. J., Chen, R. O., Brownstein, B. H., Cobb, J. P., et al. (2005) · Nature · doi:10.1038/nature03985 · Cited by 1,429 · see citing works
Mechanisms of cytochrome c release from mitochondria
Garrido, C., Galluzzi, L., Brunet, M., Puig, P., Mirjolet, C., & Kroemer, G. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401950 · Cited by 1,394 · see citing works
Effect of Cyclosporine on Reperfusion Injury in Acute Myocardial Infarction
Piot, C. A., Croisille, P., Staat, P., Thibault, H., Rioufol, G., Mewton, N., Belghiti, R. E., Cung, T. T., Bonnefoy‐Cudraz, E., Angoulvant, D., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa071142 · Cited by 1,339 · see citing works
Calcium cycling and signaling in cardiac myocytes.
Bers, D. (2008) · Annual Review of Physiology · doi:10.1146/annurev.physiol.70.113006.100455 · Cited by 1,386 · see citing works
Mitochondrial Oxidative Stress: Implications for Cell Death
Orrenius, S., Gogvadze, V. G., & Zhivotovsky, B. (2006) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.47.120505.105122 · Cited by 1,266 · see citing works
Mitochondria and the Autophagy–Inflammation–Cell Death Axis in Organismal Aging
Green, D. R., Galluzzi, L., & Kroemer, G. (2011) · Science · doi:10.1126/science.1201940 · Cited by 1,245 · 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
13 reasons why the brain is susceptible to oxidative stress
Cobley, J. N., Fiorello, M. L., & Bailey, D. M. (2018) · Redox Biology · doi:10.1016/j.redox.2018.01.008 · Cited by 1,215 · see citing works
Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis
Pinton, P., Giorgi, C., Siviero, R., Zecchini, E., & Rizzuto, R. (2008) · Oncogene · doi:10.1038/onc.2008.308 · Cited by 1,145 · see citing works
Cardiotoxicity of the cancer therapeutic agent imatinib mesylate
Kerkelä, R., Grazette, L. P., Yacobi, R., Iliescu, C., Patten, R. D., Beahm, C., Walters, B. M., Shevtsov, S. P., Pesant, S., Clubb, F. J., et al. (2006) · Nature Medicine · doi:10.1038/nm1446 · Cited by 1,157 · see citing works
Cell Death SignalingPreprint
Green, D. R., & Llambi, F. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a006080 · Cited by 1,117 · see citing works
Linkermann, A., & Green, D. R. (2014) · New England Journal of Medicine · doi:10.1056/nejmra1310050 · Cited by 1,103 · see citing works
BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis
McArthur, K., Whitehead, L. W., Heddleston, J. M., Li, L., Padman, B. S., Oorschot, V., Geoghegan, N. D., Chappaz, S., Davidson, S., San Chin, H., et al. (2018) · Science · doi:10.1126/science.aao6047 · Cited by 1,072 · see citing works
Cell death by necrosis: towards a molecular definition
Golstein, P., & Kroemer, G. (2007) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.11.001 · Cited by 1,044 · see citing works
Essential versus accessory aspects of cell death: recommendations of the NCCD 2015
Galluzzi, L., Bravo-San Pedro, J. M., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Alnemri, E. S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., et al. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.137 · Cited by 1,002 · see citing works
Compromised MAPK signaling in human diseases: an update
Kim, E., & Choi, E. (2015) · Archives of Toxicology · doi:10.1007/s00204-015-1472-2 · Cited by 1,017 · see citing works
Role of BNIP3 and NIX in cell death, autophagy, and mitophagy
Zhang, J., & Ney, P. A. (2009) · Cell Death & Differentiation · doi:10.1038/cdd.2009.16 · Cited by 1,021 · see citing works
Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death
Baines, C. P., Kaiser, R. A., Sheiko, T., Craigen, W. J., & Molkentin, J. D. (2007) · Nature Cell Biology · doi:10.1038/ncb1575 · Cited by 971 · see citing works
Self-citationMechanisms of Acetaminophen-Induced Liver Necrosis
Hinson, J., Roberts, D. W., & James, L. P. (2009) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-00663-0_12 · Cited by 993 · see citing works
Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease
Re, D. P. D., Amgalan, D., Linkermann, A., Liu, Q., & Kitsis, R. N. (2019) · Physiological Reviews · doi:10.1152/physrev.00022.2018 · Cited by 979 · see citing works
Jaeschke, H., McGill, M. R., & Ramachandran, A. (2012) · Drug Metabolism Reviews · doi:10.3109/03602532.2011.602688 · Cited by 972 · see citing works
Mitochondria take center stage in aging and neurodegeneration
Beal, M. F. (2005) · Annals of Neurology · doi:10.1002/ana.20624 · Cited by 957 · see citing works
Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions
Qin, C., Yang, S., Chu, Y., Zhang, H., Pang, X., Chen, L., Zhou, L., Chen, M., Tian, D., & Wang, W. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01064-1 · Cited by 971 · see citing works
Du, H., Guo, L., Fang, F., Chen, D., Sosunov, A. A., McKhann, G. M., Yan, Y., Wang, C., Zhang, H., Molkentin, J. D., et al. (2008) · Nature Medicine · doi:10.1038/nm.1868 · Cited by 935 · see citing works
Self-citationWhat is the mitochondrial permeability transition pore?
Halestrap, A. P. (2009) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2009.02.021 · Cited by 935 · see citing works
Dimers of mitochondrial ATP synthase form the permeability transition pore
Giorgio, V., von Stockum, S., Antoniel, M., Fabbro, A., Fogolari, F., Forte, M. A., Glick, G. D., Petronilli, V., Zoratti, M., Szabó, I., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217823110 · Cited by 924 · see citing works
Necrotic death as a cell fatePreprint
Zong, W., & Thompson, C. B. (2006) · Genes & Development · doi:10.1101/gad.1376506 · Cited by 920 · see citing works
Kregel, K. C., & Zhang, H. J. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00327.2006 · Cited by 883 · see citing works
Cellular and molecular mechanisms of mitochondrial function
Osellame, L. D., Blacker, T. S., & Duchen, M. R. (2012) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2012.05.003 · Cited by 871 · see citing works
Mitochondria as a therapeutic target for common pathologies
Murphy, M. P., & Hartley, R. C. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.174 · Cited by 832 · see citing works
Apoptotic Pathways: Ten Minutes to Dead
Green, D. R. (2005) · Cell · doi:10.1016/j.cell.2005.05.019 · Cited by 826 · see citing works
Schinzel, A. C., Takeuchi, O., Huang, Z., Fisher, J. K., Zhou, Z., Rubens, J., Hetz, C., Danial, N. N., Moskowitz, M. A., & Korsmeyer, S. J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505294102 · Cited by 820 · see citing works
CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress–induced myocardial necroptosis
Zhang, T., Zhang, Y., Cui, M., Jin, L., Wang, Y., Lv, F., Liu, Y., Zheng, W., Shang, H., Zhang, J., et al. (2016) · Nature Medicine · doi:10.1038/nm.4017 · Cited by 790 · see citing works
Mitochondrial function as a therapeutic target in heart failure
Brown, D. A., Perry, J. B., Allen, M. E., Sabbah, H. N., Stauffer, B. L., Shaikh, S. R., Cleland, J. G. F., Colucci, W. S., Butler, J., Voors, A. A., et al. (2016) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2016.203 · Cited by 811 · see citing works
Intracellular Ca2+ Sensing: Its Role in Calcium Homeostasis and Signaling
Bagur, R., & Hajnóczky, G. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.05.028 · Cited by 815 · see citing works
Kubli, D. A., & Gustafsson, Å. B. (2012) · Circulation Research · doi:10.1161/circresaha.112.265819 · Cited by 792 · see citing works
NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart
Kuroda, J., Ago, T., Matsushima, S., Zhai, P., Schneider, M. D., & Sadoshima, J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002178107 · Cited by 772 · see citing works
Cell Death and Cell Death Responses in Liver Disease: Mechanisms and Clinical Relevance
Luedde, T., Kaplowitz, N., & Schwabe, R. F. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.07.018 · Cited by 760 · see citing works
Cell Death in the Pathogenesis of Heart Disease: Mechanisms and Significance
Whelan, R. S., Kaplinskiy, V., & Kitsis, R. N. (2010) · Annual Review of Physiology · doi:10.1146/annurev.physiol.010908.163111 · Cited by 751 · see citing works
p53 Opens the Mitochondrial Permeability Transition Pore to Trigger Necrosis
Vaseva, A. V., Marchenko, N. D., Ji, K., Tsirka, S. E., Holzmann, S., & Moll, U. M. (2012) · Cell · doi:10.1016/j.cell.2012.05.014 · Cited by 740 · see citing works
Kalogeris, T. J., Baines, C. P., Krenz, M., & Korthuis, R. J. (2016) · Comprehensive physiology · doi:10.1002/cphy.c160006 · Cited by 841 · see citing works
Self-citationMolecular effectors of multiple cell death pathways initiated by photodynamic therapy
Buytaert, E., Dewaele, M., & Agostinis, P. (2007) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2007.07.001 · Cited by 749 · see citing works
Necroptosis: Mechanisms and Relevance to Disease
Galluzzi, L., Kepp, O., Chan, F. K.-M., & Kroemer, G. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-052016-100247 · Cited by 721 · see citing works
Caspase-independent cell death
Kroemer, G., & Martin, S. J. (2005) · Nature Medicine · doi:10.1038/nm1263 · Cited by 719 · see citing works
Festjens, N., Vanden Berghe, T., & Vandenabeele, P. (2006) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2006.06.014 · Cited by 710 · see citing works
Superoxide flashes in single mitochondria
Wang, W., Fang, H., Groom, L., Cheng, A., Zhang, W., Liu, J., Wang, X., Li, K., Han, P., Zheng, M., et al. (2008) · Cell · doi:10.1016/j.cell.2008.06.017 · Cited by 715 · see citing works
Cyclosporine before PCI in Patients with Acute Myocardial Infarction
Cung, T.-T., Morel, O., Cayla, G., Rioufol, G., Garcia-Dorado, D., Angoulvant, D., Bonnefoy-Cudraz, E., Guérin, P., Elbaz, M., Delarche, N., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1505489 · Cited by 713 · see citing works
Apoptosis and Necrosis in the Liver: A Tale of Two Deaths?
Malhi, H., Gores, G. J., & Lemasters, J. J. (2006) · Hepatology · doi:10.1002/hep.21062 · Cited by 688 · see citing works
Mitochondria, oxidative metabolism and cell death in stroke
Sims, N. R., & Muyderman, H. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.09.003 · Cited by 675 · see citing works
Metabolic control of cell death
Green, D. R., Galluzzi, L., & Kroemer, G. (2014) · Science · doi:10.1126/science.1250256 · Cited by 661 · see citing works
Regulated necrosis: disease relevance and therapeutic opportunities
Conrad, M., Angeli, J. P. F., Vandenabeele, P., & Stockwell, B. R. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.6 · Cited by 630 · see citing works
Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario
Chipuk, J. E., Bouchier-Hayes, L., & Green, D. R. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401963 · Cited by 631 · see citing works
The mitochondrial permeability transition from<i>in vitro</i>artifact to disease target
Bernardi, P., Krauskopf, A., Basso, E., Petronilli, V., Blalchy‐Dyson, E., Di Lisa, F., & Forte, M. A. (2006) · The FEBS Journal · doi:10.1111/j.1742-4658.2006.05213.x · Cited by 627 · see citing works
Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model
Du, H., Guo, L., Yan, S., Sosunov, A. A., McKhann, G. M., & ShiDu Yan, S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006586107 · Cited by 704 · see citing works
Roca, F. J., & Ramakrishnan, L. (2013) · Cell · doi:10.1016/j.cell.2013.03.022 · Cited by 592 · see citing works
Pathophysiology of Myocardial Infarction
Frangogiannis, N. G. (2015) · Comprehensive physiology · doi:10.1002/cphy.c150006 · Cited by 717 · see citing works
Mitochondria in health, disease, and aging
Harrington, J. S., Ryter, S. W., Plataki, M. E., Price, D. R., & Choi, A. M. K. (2023) · Physiological Reviews · doi:10.1152/physrev.00058.2021 · Cited by 622 · 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
Wang, P., & Heitman, J. (2005) · Genome biology · doi:10.1186/gb-2005-6-7-226 · Cited by 598 · see citing works
Alavian, K. N., Beutner, G., Lazrove, E., Sacchetti, S., Park, H., Licznerski, P., Li, H., Nabili, P., Hockensmith, K., Graham, M. M., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1401591111 · Cited by 595 · see citing works
Deniaud, A., Sharaf el dein, O., Maillier, E., Poncet, D., Kroemer, G., Lemaire, C., & Brenner, C. (2008) · Oncogene · doi:10.1038/sj.onc.1210638 · Cited by 586 · see citing works
Bernardi, P., Rasola, A., Forte, M. A., & Lippe, G. (2015) · Physiological Reviews · doi:10.1152/physrev.00001.2015 · Cited by 586 · see citing works
Ribas, V., García‐Ruiz, C., & Fernández-Checa, J. C. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00151 · Cited by 572 · see citing works
Mitochondrial permeability transition in Ca2+-dependent apoptosis and necrosis
Rasola, A., & Bernardi, P. (2011) · Cell Calcium · doi:10.1016/j.ceca.2011.04.007 · Cited by 563 · see citing works
Cellular and Molecular Mechanisms of Liver Injury
Malhi, H., & Gores, G. J. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.03.002 · Cited by 559 · see citing works
Role of the mitochondrial membrane permeability transition in cell death
Tsujimoto, Y., & Shimizu, S. (2006) · APOPTOSIS · doi:10.1007/s10495-006-0525-7 · Cited by 559 · see citing works
Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis
Riley, J. S., Quarato, G., Cloix, C., Lopez, J., O'Prey, J., Pearson, M., Chapman, J., Sesaki, H., Carlin, L. M., Passos, J. F., et al. (2018) · The EMBO Journal · doi:10.15252/embj.201899238 · Cited by 551 · see citing works
Calcium, mitochondria and reperfusion injury: a pore way to die
Halestrap, A. P. (2006) · Biochemical Society Transactions · doi:10.1042/bst20060232 · Cited by 558 · see citing works
Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury
Linkermann, A., Bräsen, J. H., Darding, M., Jin, M. K., Sanz, A. B., Heller, J.-O., Zen, F. D., Weinlich, R., Ortíz, A., Walczak, H., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1305538110 · Cited by 568 · see citing works
Molecular mechanisms and consequences of mitochondrial permeability transition
Bonora, M., Giorgi, C., & Pinton, P. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00433-y · Cited by 549 · see citing works
Hafner, A. V., Dai, J., Gomes, A. P., Xiao, C., Palmeira, C. M., Rosenzweig, A., & Sinclair, D. A. (2010) · Aging · doi:10.18632/aging.100252 · Cited by 547 · see citing works
Mitochondrial Control of Cellular Life, Stress, and Death
Galluzzi, L., Kepp, O., Trojel‐Hansen, C., & Kroemer, G. (2012) · Circulation Research · doi:10.1161/circresaha.112.268946 · Cited by 545 · see citing works
Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy
Hamacher-Brady, A., Brady, N. R., Logue, S. E., Sayen, M. R., Jinno, M., Kirshenbaum, L. A., Gottlieb, R. A., & Gustafsson, Å. B. (2007) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401936 · Cited by 609 · see citing works
Self-citationDrug-induced mitochondrial dysfunction and cardiotoxicity
Varga, Z. V., Ferdinandy, P., Liaudet, L., & Pacher, P. (2015) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00554.2015 · Cited by 535 · see citing works
Calcium and mitochondria in the regulation of cell death
Orrenius, S., Gogvadze, V. G., & Zhivotovsky, B. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.01.137 · Cited by 530 · see citing works
Calcium and cell death mechanisms: A perspective from the cell death community
Zhivotovsky, B., & Orrenius, S. (2011) · Cell Calcium · doi:10.1016/j.ceca.2011.03.003 · Cited by 527 · see citing works
Cellular Mechanisms Underlying the Formation of Circulating Microparticles
Morel, O., Jesel, L., Freyssinet, J., & Toti, F. (2010) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.200956 · Cited by 525 · see citing works
Regulated cell death and inflammation: an auto-amplification loop causes organ failure
Linkermann, A., Stockwell, B. R., Krautwald, S., & Anders, H.-J. (2014) · Nature Reviews Immunology · doi:10.1038/nri3743 · Cited by 522 · see citing works
Chemotherapeutic Approaches for Targeting Cell Death Pathways
Ricci, M., & Zong, W. (2006) · The Oncologist · doi:10.1634/theoncologist.11-4-342 · Cited by 512 · see citing works
Rasola, A., & Bernardi, P. (2007) · APOPTOSIS · doi:10.1007/s10495-007-0723-y · Cited by 507 · see citing works
Mitochondria and Endothelial Function
Kluge, M. A., Fetterman, J. L., & Vita, J. A. (2013) · Circulation Research · doi:10.1161/circresaha.111.300233 · Cited by 508 · see citing works
Roberts, D. J., & Miyamoto, S. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.173 · Cited by 507 · see citing works
Bernardi, P., & Lisa, F. D. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.09.023 · Cited by 499 · see citing works
Song, M., Mihara, K., Chen, Y., Scorrano, L., & Dorn, G. W. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2014.12.011 · Cited by 482 · see citing works
Self-citationCardiomyocyte death: mechanisms and translational implications
Chiong, M., Wang, Z. V., Pedrozo, Z., Cao, D. J., Troncoso, R., Ibacache, M. E., Criollo, A., Nemchenko, A., Hill, J. A., & Lavandero, S. (2011) · Cell Death and Disease · doi:10.1038/cddis.2011.130 · Cited by 492 · see citing works
- Authors
- Baines, C. P., Kaiser, R. A., Purcell, N. H., Blair, N. S., Osinska, H., Hambleton, M. A., Brunskill, E. W., Sayen, M. R., Gottlieb, R. A., Dorn, G. W., Robbins, J., & Molkentin, J. D.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Scripps Research Institute (US)
- Corresponding author
- Molkentin, Jeffery D.
- ORCID
- Venue
- Nature
- Published
- 2005-03
- Volume
- 434
- Issue
- 7033
- Pages
- 658-662
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2074800090
- Cited by
- 2,280
- References
- 28
- Citations by year
- 2026: 65 · 2025: 72 · 2024: 50 · 2023: 73 · 2022: 82 · 2021: 94 · 2020: 106 · 2019: 85 · 2018: 111 · 2017: 108 · 2016: 122 · 2015: 119 · 2014: 144 · 2013: 114 · 2012: 156
- FWCI
- 43.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- cyclophilin D, mitochondrial permeability transition, mitochondrial swelling, ischemia-reperfusion injury, calcium overload, oxidative stress, cell death, Bcl-2 family proteins, staurosporine, TNF-α, adenine nucleotide translocase, voltage-dependent anion channel, peptidyl-prolyl isomerase, heart, hepatocytes, fibroblasts
- MeSH terms
- Peptidyl-Prolyl Isomerase F, Adenoviridae, Animals, Atractyloside, Brain, Calcium, Carrier Proteins, Cells, Cultured, Fibroblasts, Hydrogen Peroxide, Liver, Mice, Transgenic, Mitochondria, Mitochondrial Swelling, Cell Death, Gene Deletion, Mice, Knockout, Oxidative Stress, Proto-Oncogene Proteins c-bcl-2, Caspases, Cyclophilins, Myocytes, Cardiac, Cytochromes c, BH3 Interacting Domain Death Agonist Protein, bcl-2-Associated X Protein, Mice
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
