Cyclosporin A Increases Mitochondrial Buffering of Calcium: An Additional Mechanism in Delaying Mitochondrial Permeability Transition Pore Opening
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Animals
2.3. Mitochondria Isolation
2.4. Experimental Groups and Protocols
2.5. Mitochondrial Function Measurements
2.6. Measurements of Free Ca2+
2.7. Calculation of Mitochondrial Ca2+ Buffering Capacity
2.8. Measurement of ΔΨm, Redox State (NADH) and Matrix pH
2.9. Depletion of Endogenous Mitochondrial Phosphate
2.10. Statistical Analyses
3. Results
3.1. Effect of CsA on Extra-Matrix Free [Ca2+]
3.2. Effect of CsA on Matrix Free [Ca2+] Handling
3.3. Effect of CsA on Ca2+-Mediated Changes in ΔΨm, NADH, and Matrix pH
3.4. Time Dependent Effect of CsA Addition on Rescue of Mitochondria from Imminent Ca2+-Induced mPTP Opening
3.5. Role of Inorganic Phosphate in CsA-Induced [Ca2+]m Regulation.
4. Discussion
4.1. CsA-Mediated Inhibition of mPTP Opening Relates to the ss[Ca2+]m
4.2. Underlying Mechanism of the CsA-Mediated [Ca2+]m Regulation
4.3. CsA vs. ADP; As a Regulator of [Ca2+]m
4.4. Implication of CsA-Mediated Ca2+ Buffering on Mitochondrial Bioenergetics
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Denton, R.M.; McCormack, J.G. The calcium sensitive dehydrogenases of vertebrate mitochondria. Cell Calcium 1986, 7, 377–386. [Google Scholar] [CrossRef]
- Jouaville, L.S.; Pinton, P.; Bastianutto, C.; Rutter, G.A.; Rizzuto, R. Regulation of mitochondrial ATP synthesis by calcium: Evidence for a long-term metabolic priming. Proc. Natl. Acad. Sci. USA 1999, 96, 13807–13812. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bernardi, P. Mitochondrial transport of cations: Channels, exchangers, and permeability transition. Physiol. Rev. 1999, 79, 1127–1155. [Google Scholar] [CrossRef] [PubMed]
- Hajnoczky, G.; Csordas, G.; Das, S.; Garcia-Perez, C.; Saotome, M.; Sinha Roy, S.; Yi, M. Mitochondrial calcium signalling and cell death: Approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis. Cell Calcium 2006, 40, 553–560. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brookes, P.S.; Yoon, Y.; Robotham, J.L.; Anders, M.W.; Sheu, S.S. Calcium, ATP, and ROS: A mitochondrial love-hate triangle. Am. J. Physiol. Cell Physiol. 2004, 287, C817–C833. [Google Scholar] [CrossRef] [PubMed]
- O’Rourke, B.; Cortassa, S.; Aon, M.A. Mitochondrial ion channels: Gatekeepers of life and death. Physiology (Bethesda) 2005, 20, 303–315. [Google Scholar] [CrossRef]
- Camara, A.K.; Lesnefsky, E.J.; Stowe, D.F. Potential therapeutic benefits of strategies directed to mitochondria. Antioxid. Redox Signal. 2010, 13, 279–347. [Google Scholar] [CrossRef]
- Gunter, T.E.; Buntinas, L.; Sparagna, G.; Eliseev, R.; Gunter, K. Mitochondrial calcium transport: Mechanisms and functions. Cell Calcium 2000, 28, 285–296. [Google Scholar] [CrossRef]
- Baughman, J.M.; Perocchi, F.; Girgis, H.S.; Plovanich, M.; Belcher-Timme, C.A.; Sancak, Y.; Bao, X.R.; Strittmatter, L.; Goldberger, O.; Bogorad, R.L.; et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 2011, 476, 341–345. [Google Scholar] [CrossRef] [Green Version]
- De Stefani, D.; Raffaello, A.; Teardo, E.; Szabo, I.; Rizzuto, R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 2011, 476, 336–340. [Google Scholar] [CrossRef]
- Mitchell, P. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 1961, 191, 144–148. [Google Scholar] [CrossRef] [PubMed]
- Mitchell, P. Keilin’s respiratory chain concept and its chemiosmotic consequences. Science 1979, 206, 1148–1159. [Google Scholar] [CrossRef] [PubMed]
- Greenawalt, J.W.; Rossi, C.S.; Lehninger, A.L. Effect of Active Accumulation of Calcium and Phosphate Ions on the Structure of Rat Liver Mitochondria. J. Cell Biol. 1964, 23, 21–38. [Google Scholar] [CrossRef] [PubMed]
- Chalmers, S.; Nicholls, D.G. The relationship between free and total calcium concentrations in the matrix of liver and brain mitochondria. J. Biol. Chem. 2003, 278, 19062–19070. [Google Scholar] [CrossRef] [PubMed]
- Starkov, A.A. The molecular identity of the mitochondrial Ca2+ sequestration system. FEBS J. 2010, 277, 3652–3663. [Google Scholar] [CrossRef] [Green Version]
- Carafoli, E.; Tiozzo, R.; Lugli, G.; Crovetti, F.; Kratzing, C. The release of calcium from heart mitochondria by sodium. J. Mol. Cell. Cardiol. 1974, 6, 361–371. [Google Scholar] [CrossRef]
- Palty, R.; Silverman, W.F.; Hershfinkel, M.; Caporale, T.; Sensi, S.L.; Parnis, J.; Nolte, C.; Fishman, D.; Shoshan-Barmatz, V.; Herrmann, S.; et al. NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc. Natl. Acad. Sci. USA 2010, 107, 436–441. [Google Scholar] [CrossRef]
- Boyman, L.; Williams, G.S.; Khananshvili, D.; Sekler, I.; Lederer, W.J. NCLX: The mitochondrial sodium calcium exchanger. J. Mol. Cell. Cardiol. 2013, 59, 205–213. [Google Scholar] [CrossRef] [Green Version]
- Haumann, J.; Camara, A.K.S.; Gadicherla, A.K.; Navarro, C.D.; Boelens, A.D.; Blomeyer, C.A.; Dash, R.K.; Boswell, M.R.; Kwok, W.M.; Stowe, D.F. Slow Ca(2+) Efflux by Ca(2+)/H(+) Exchange in Cardiac Mitochondria Is Modulated by Ca(2+) Re-uptake via MCU, Extra-Mitochondrial pH, and H(+) Pumping by FOF1-ATPase. Front. Physiol. 2018, 9, 1914. [Google Scholar] [CrossRef]
- Bernardi, P.; Vassanelli, S.; Veronese, P.; Colonna, R.; Szabo, I.; Zoratti, M. Modulation of the mitochondrial permeability transition pore. Effect of protons and divalent cations. J. Biol. Chem. 1992, 267, 2934–2939. [Google Scholar]
- Szabo, I.; Zoratti, M. The mitochondrial megachannel is the permeability transition pore. J. Bioenerg. Biomembr. 1992, 24, 111–117. [Google Scholar] [CrossRef] [PubMed]
- Crompton, M. The mitochondrial permeability transition pore and its role in cell death. Biochem. J. 1999, 341 Pt 2, 233–249. [Google Scholar] [CrossRef] [PubMed]
- Kim, J.S.; He, L.; Lemasters, J.J. Mitochondrial permeability transition: A common pathway to necrosis and apoptosis. Biochem. Biophys. Res. Commun. 2003, 304, 463–470. [Google Scholar] [CrossRef]
- Nakagawa, T.; Shimizu, S.; Watanabe, T.; Yamaguchi, O.; Otsu, K.; Yamagata, H.; Inohara, H.; Kubo, T.; Tsujimoto, Y. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 2005, 434, 652–658. [Google Scholar] [CrossRef] [PubMed]
- Basso, E.; Fante, L.; Fowlkes, J.; Petronilli, V.; Forte, M.A.; Bernardi, P. Properties of the permeability transition pore in mitochondria devoid of Cyclophilin, D. J. Biol. Chem. 2005, 280, 18558–18561. [Google Scholar] [CrossRef] [PubMed]
- 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.; et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 2005, 434, 658–662. [Google Scholar] [CrossRef]
- Hunter, D.R.; Haworth, R.A. The Ca2+-induced membrane transition in mitochondria. I. The protective mechanisms. Arch. Biochem. Biophys. 1979, 195, 453–459. [Google Scholar] [CrossRef]
- Halestrap, A.P.; Connern, C.P.; Griffiths, E.J.; Kerr, P.M. Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury. Mol. Cell. Biochem. 1997, 174, 167–172. [Google Scholar] [CrossRef]
- Haumann, J.; Dash, R.K.; Stowe, D.F.; Boelens, A.D.; Beard, D.A.; Camara, A.K. Mitochondrial free [Ca2+] increases during ATP/ADP antiport and ADP phosphorylation: Exploration of mechanisms. Biophys. J. 2010, 99, 997–1006. [Google Scholar] [CrossRef]
- Sokolova, N.; Pan, S.; Provazza, S.; Beutner, G.; Vendelin, M.; Birkedal, R.; Sheu, S.S. ADP protects cardiac mitochondria under severe oxidative stress. PLoS ONE 2013, 8, e83214. [Google Scholar] [CrossRef]
- Griffiths, E.J.; Halestrap, A.P. Further evidence that cyclosporin A protects mitochondria from calcium overload by inhibiting a matrix peptidyl-prolyl cis-trans isomerase. Implications for the immunosuppressive and toxic effects of cyclosporin. Biochem. J. 1991, 274 Pt 2, 611–614. [Google Scholar] [CrossRef] [PubMed]
- Waldmeier, P.C.; Feldtrauer, J.J.; Qian, T.; Lemasters, J.J. Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM811. Mol. Pharmacol. 2002, 62, 22–29. [Google Scholar] [CrossRef]
- Altschuld, R.A.; Hohl, C.M.; Castillo, L.C.; Garleb, A.A.; Starling, R.C.; Brierley, G.P. Cyclosporin inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes. Am. J. Physiol. 1992, 262, H1699–H1704. [Google Scholar] [CrossRef]
- Wei, A.C.; Liu, T.; Cortassa, S.; Winslow, R.L.; O’Rourke, B. Mitochondrial Ca2+ influx and efflux rates in guinea pig cardiac mitochondria: Low and high affinity effects of cyclosporine A. Biochim. Biophys. Acta 2011, 1813, 1373–1381. [Google Scholar] [CrossRef] [PubMed]
- Blomeyer, C.A.; Bazil, J.N.; Stowe, D.F.; Pradhan, R.K.; Dash, R.K.; Camara, A.K. Dynamic buffering of mitochondrial Ca2+ during Ca2+ uptake and Na+-induced Ca2+ release. J. Bioenerg. Biomembr. 2013, 45, 189–202. [Google Scholar] [CrossRef] [PubMed]
- Aldakkak, M.; Stowe, D.F.; Dash, R.K.; Camara, A.K. Mitochondrial handling of excess Ca2+ is substrate-dependent with implications for reactive oxygen species generation. Free Radic. Biol. Med. 2013, 56, 193–203. [Google Scholar] [CrossRef] [PubMed]
- Agarwal, B.; Dash, R.K.; Stowe, D.F.; Bosnjak, Z.J.; Camara, A.K. Isoflurane modulates cardiac mitochondrial bioenergetics by selectively attenuating respiratory complexes. Biochim. Biophys. Acta 2014, 1837, 354–365. [Google Scholar] [CrossRef] [PubMed]
- Blomeyer, C.A.; Bazil, J.N.; Stowe, D.F.; Dash, R.K.; Camara, A.K. Mg(2+) differentially regulates two modes of mitochondrial Ca(2+) uptake in isolated cardiac mitochondria: Implications for mitochondrial Ca(2+) sequestration. J. Bioenerg. Biomembr. 2016, 48, 175–188. [Google Scholar] [CrossRef]
- Boelens, A.D.; Pradhan, R.K.; Blomeyer, C.A.; Camara, A.K.; Dash, R.K.; Stowe, D.F. Extra-matrix Mg2+ limits Ca2+ uptake and modulates Ca2+ uptake-independent respiration and redox state in cardiac isolated mitochondria. J. Bioenerg. Biomembr. 2013, 45, 203–218. [Google Scholar] [CrossRef]
- Scaduto, R.C., Jr.; Grotyohann, L.W. Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys. J. 1999, 76, 469–477. [Google Scholar] [CrossRef]
- Grynkiewicz, G.; Poenie, M.; Tsien, R.Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J. Biol. Chem. 1985, 260, 3440–3450. [Google Scholar] [PubMed]
- Bazil, J.N.; Blomeyer, C.A.; Pradhan, R.K.; Camara, A.K.; Dash, R.K. Modeling the calcium sequestration system in isolated guinea pig cardiac mitochondria. J. Bioenerg. Biomembr. 2013, 45, 177–188. [Google Scholar] [CrossRef] [PubMed]
- Zoccarato, F.; Nicholls, D. The role of phosphate in the regulation of the independent calcium-efflux pathway of liver mitochondria. Eur. J. Biochem. 1982, 127, 333–338. [Google Scholar] [CrossRef] [PubMed]
- Wei, A.C.; Liu, T.; O’Rourke, B. Dual Effect of Phosphate Transport on Mitochondrial Ca2+ Dynamics. J. Biol. Chem. 2015, 290, 16088–16098. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wei, A.C.; Liu, T.; Winslow, R.L.; O’Rourke, B. Dynamics of matrix-free Ca2+ in cardiac mitochondria: Two components of Ca2+ uptake and role of phosphate buffering. J. Gen. Physiol. 2012, 139, 465–478. [Google Scholar] [CrossRef] [PubMed]
- Glancy, B.; Balaban, R.S. Role of mitochondrial Ca2+ in the regulation of cellular energetics. Biochemistry 2012, 51, 2959–2973. [Google Scholar] [CrossRef] [PubMed]
- Vasington, F.D.; Murphy, J.V. Ca ion uptake by rat kidney mitochondria and its dependence on respiration and phosphorylation. J. Biol. Chem. 1962, 237, 2670–2677. [Google Scholar] [PubMed]
- Chinopoulos, C.; Adam-Vizi, V. Mitochondrial Ca2+ sequestration and precipitation revisited. FEBS J. 2010, 277, 3637–3651. [Google Scholar] [CrossRef] [PubMed]
- Harris, E.J.; Zaba, B. The phosphate requirement for Ca2+-uptake by heart and liver mitochondria. FEBS Lett. 1977, 79, 284–290. [Google Scholar] [CrossRef]
- Nicholls, D.G.; Chalmers, S. The integration of mitochondrial calcium transport and storage. J. Bioenerg. Biomembr. 2004, 36, 277–281. [Google Scholar] [CrossRef]
- Kristian, T.; Pivovarova, N.B.; Fiskum, G.; Andrews, S.B. Calcium-induced precipitate formation in brain mitochondria: Composition, calcium capacity, and retention. J. Neurochem. 2007, 102, 1346–1356. [Google Scholar] [CrossRef]
- Kushnareva, Y.E.; Haley, L.M.; Sokolove, P.M. The role of low (<or = 1 mM) phosphate concentrations in regulation of mitochondrial permeability: Modulation of matrix free Ca2+ concentration. Arch. Biochem. Biophys. 1999, 363, 155–162. [Google Scholar] [CrossRef] [PubMed]
- Malyala, S.; Zhang, Y.; Strubbe, J.O.; Bazil, J.N. Calcium phosphate precipitation inhibits mitochondrial energy metabolism. PLoS Comput. Biol. 2019, 15, e1006719. [Google Scholar] [CrossRef] [PubMed]
- Abramov, A.Y.; Fraley, C.; Diao, C.T.; Winkfein, R.; Colicos, M.A.; Duchen, M.R.; French, R.J.; Pavlov, E. Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death. Proc. Natl. Acad. Sci. USA 2007, 104, 18091–18096. [Google Scholar] [CrossRef] [Green Version]
- Seidlmayer, L.K.; Gomez-Garcia, M.R.; Blatter, L.A.; Pavlov, E.; Dedkova, E.N. Inorganic polyphosphate is a potent activator of the mitochondrial permeability transition pore in cardiac myocytes. J. Gen. Physiol. 2012, 139, 321–331. [Google Scholar] [CrossRef] [Green Version]
- Chavez, E.; Moreno-Sanchez, R.; Zazueta, C.; Rodriguez, J.S.; Bravo, C.; Reyes-Vivas, H. On the protection by inorganic phosphate of calcium-induced membrane permeability transition. J. Bioenerg. Biomembr. 1997, 29, 571–577. [Google Scholar] [CrossRef] [PubMed]
- Basso, E.; Petronilli, V.; Forte, M.A.; Bernardi, P. Phosphate is essential for inhibition of the mitochondrial permeability transition pore by cyclosporin A and by cyclophilin D ablation. J. Biol. Chem. 2008, 283, 26307–26311. [Google Scholar] [CrossRef] [PubMed]
- McGee, A.M.; Baines, C.P. Phosphate is not an absolute requirement for the inhibitory effects of cyclosporin A or cyclophilin D deletion on mitochondrial permeability transition. Biochem. J. 2012, 443, 185–191. [Google Scholar] [CrossRef] [Green Version]
- Varanyuwatana, P.; Halestrap, A.P. The roles of phosphate and the phosphate carrier in the mitochondrial permeability transition pore. Mitochondrion 2012, 12, 120–125. [Google Scholar] [CrossRef]
- Carafoli, E.; Rossi, C.S.; Lehninger, A.L. Uptake of Adenine Nucleotides by Respiring Mitochondria during Active Accumulation of Ca++ and Phosphate. J. Biol. Chem. 1965, 240, 2254–2261. [Google Scholar]
- Michailova, A.; McCulloch, A. Model study of ATP and ADP buffering, transport of Ca(2+) and Mg(2+), and regulation of ion pumps in ventricular myocyte. Biophys. J. 2001, 81, 614–629. [Google Scholar] [CrossRef]
- Litsky, M.L.; Pfeiffer, D.R. Regulation of the mitochondrial Ca2+ uniporter by external adenine nucleotides: The uniporter behaves like a gated channel which is regulated by nucleotides and divalent cations. Biochemistry 1997, 36, 7071–7080. [Google Scholar] [CrossRef] [PubMed]
- Traba, J.; Del Arco, A.; Duchen, M.R.; Szabadkai, G.; Satrustegui, J. SCaMC-1 promotes cancer cell survival by desensitizing mitochondrial permeability transition via ATP/ADP-mediated matrix Ca(2+) buffering. Cell Death Differ. 2012, 19, 650–660. [Google Scholar] [CrossRef] [PubMed]
- Devenish, R.J.; Prescott, M.; Boyle, G.M.; Nagley, P. The oligomycin axis of mitochondrial ATP synthase: OSCP and the proton channel. J. Bioenerg. Biomembr. 2000, 32, 507–515. [Google Scholar] [CrossRef] [PubMed]
- Genge, B.R.; Wu, L.N.; Wuthier, R.E. In vitro modeling of matrix vesicle nucleation: Synergistic stimulation of mineral formation by annexin A5 and phosphatidylserine. J. Biol. Chem. 2007, 282, 26035–26045. [Google Scholar] [CrossRef] [PubMed]
- Bandorowicz-Pikula, J.; Buchet, R.; Pikula, S. Annexins as nucleotide-binding proteins: Facts and speculations. Bioessays 2001, 23, 170–178. [Google Scholar] [CrossRef]
- McCormack, J.G.; Denton, R.M. Intracellular calcium ions and intramitochondrial Ca2+ in the regulation of energy metabolism in mammalian tissues. Proc. Nutr. Soc. 1990, 49, 57–75. [Google Scholar] [CrossRef] [PubMed]
- Rutter, G.A. Ca2(+)-binding to citrate cycle dehydrogenases. Int. J. Biochem. 1990, 22, 1081–1088. [Google Scholar] [CrossRef]
- Territo, P.R.; Mootha, V.K.; French, S.A.; Balaban, R.S. Ca(2+) activation of heart mitochondrial oxidative phosphorylation: Role of the F(0)/F(1)-ATPase. Am. J. Physiol. Cell Physiol. 2000, 278, C423–C435. [Google Scholar] [CrossRef] [PubMed]
- Chinopoulos, C.; Adam-Vizi, V. The ‘ins and outs’ of Ca2+ in mitochondria. FEBS J. 2010, 277, 3621. [Google Scholar] [CrossRef] [PubMed]
- Jung, D.W.; Baysal, K.; Brierley, G.P. The sodium-calcium antiport of heart mitochondria is not electroneutral. J. Biol. Chem. 1995, 270, 672–678. [Google Scholar] [CrossRef] [PubMed]
- Kim, B.; Matsuoka, S. Cytoplasmic Na+-dependent modulation of mitochondrial Ca2+ via electrogenic mitochondrial Na+-Ca2+ exchange. J. Physiol. 2008, 586, 1683–1697. [Google Scholar] [CrossRef] [PubMed]
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Mishra, J.; Davani, A.J.; Natarajan, G.K.; Kwok, W.-M.; Stowe, D.F.; Camara, A.K.S. Cyclosporin A Increases Mitochondrial Buffering of Calcium: An Additional Mechanism in Delaying Mitochondrial Permeability Transition Pore Opening. Cells 2019, 8, 1052. https://doi.org/10.3390/cells8091052
Mishra J, Davani AJ, Natarajan GK, Kwok W-M, Stowe DF, Camara AKS. Cyclosporin A Increases Mitochondrial Buffering of Calcium: An Additional Mechanism in Delaying Mitochondrial Permeability Transition Pore Opening. Cells. 2019; 8(9):1052. https://doi.org/10.3390/cells8091052
Chicago/Turabian StyleMishra, Jyotsna, Ariea J. Davani, Gayathri K. Natarajan, Wai-Meng Kwok, David F. Stowe, and Amadou K.S. Camara. 2019. "Cyclosporin A Increases Mitochondrial Buffering of Calcium: An Additional Mechanism in Delaying Mitochondrial Permeability Transition Pore Opening" Cells 8, no. 9: 1052. https://doi.org/10.3390/cells8091052