Substrate- and Calcium-Dependent Differential Regulation of Mitochondrial Oxidative Phosphorylation and Energy Production in the Heart and Kidney
Abstract
1. Introduction
2. Materials and Methods
2.1. Mitochondrial Isolation
2.1.1. Heart Mitochondria
2.1.2. Kidney Outer Medulla (OM) Mitochondria
2.2. Mitochondrial O2 Consumption Measurement
2.3. Control of Extra-Mitochondrial free Ca2+ Concentrations
2.4. Data Analysis and Statistics
3. Results
4. Discussion
4.1. Intermediate Metabolism and Energy Production: Unique Challenges Due to Different Energy Demands of the Heart and Kidneys
4.2. Substrate-Dependent Mitochondrial Respiratory Rates for the Heart and Kidney OM with Addition of a Fixed ADP Concentration
4.3. Current Understanding of Mitochondrial Ca2+ Regulation and Regulation of Mitochondrial Substrate Transport and Energy Metabolism by Ca2+
4.4. Complex Effects of Respiratory Substrates upon Ca2+ Activation of Mitochondrial Respiration and ATP Production in the Heart and Kidney OM
4.5. Mechanisms That May Explain the Seemingly Paradoxical Inhibitory Effects of Higher Ca2+ Concentrations on Mitochondrial State 3 Respiration
4.6. Simple Kinetic Model Comparing the Activation and Inhibition Effects of Free Ca2+ on Mitochondria State 3 Respiration
5. Summary and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviation
AKGDH | Alpha-ketoglutarate dehydrogenase |
AM | Alpha-ketoglutarate + malate |
ANT | Adenine nucleotide translocase |
BSA | Bovine serum albumin |
ETC | Electron transport chain |
GM | Glutamate + malate |
IB | Isolation buffer |
IMM | Inner mitochondrial membrane |
ICDH | Isocitrate dehydrogenase |
JO2 | Oxygen consumption flux |
MAS | Malate-Aspartate shuttle |
MCU | Mitochondrial Ca2+ uniporter |
MDH | Malate dehydrogenase |
mPTP | Mitochondrial permeability transition pore |
mTAL | Medullary thick ascending limbs of loop of Henle |
NCE | Na+/Ca2+ Exchanger |
NHE | Na+/H+ Exchanger |
O2k | Oxygraph-2k |
OCR | Oxygen consumption rate |
OGDH | 2-oxo glutarate dehydrogenase |
OM | Outer medulla |
OxPhos | Oxidative Phosphorylation |
PCM | Palmitoyl-carnitine + malate |
PIC | Inorganic phosphate carrier |
PDH | Pyruvate dehydrogenase |
PM | Pyruvate + malate |
RB | Respiration buffer |
RCR | Respiratory control ratio |
ROT | Rotenone |
SD | Sprague-Dawley |
SUC | Succinate |
TCA | Tricarboxylic acid cycle |
References
- Tian, Z.; Liang, M. Renal metabolism and hypertension. Nat. Commun. 2021, 12, 963. [Google Scholar] [CrossRef]
- Bhargava, P.; Schnellmann, R.G. Mitochondrial energetics in the kidney. Nat. Rev. Nephrol. 2017, 13, 629–646. [Google Scholar] [CrossRef] [PubMed]
- Bertero, E.; Maack, C. Metabolic remodelling in heart failure. Nat. Rev. Cardiol. 2018, 15, 457–470. [Google Scholar] [CrossRef]
- Vander Heiden, M.G.; DeBerardinis, R.J. Understanding the Intersections between Metabolism and Cancer Biology. Cell 2017, 168, 657–669. [Google Scholar] [CrossRef] [PubMed]
- Nicholls, D.G.; Ferguson, S.J. Bioenergetics, 4th ed.; Academic Press: London, UK, 2013. [Google Scholar]
- Rizzuto, R.; De Stefani, D.; Raffaello, A.; Mammucari, C. Mitochondria as sensors and regulators of calcium signalling. Nat. Reviews. Mol. Cell Biol. 2012, 13, 566–578. [Google Scholar] [CrossRef] [PubMed]
- Duchen, M.R. Mitochondria and calcium: From cell signalling to cell death. J. Physiol. 2000, 529 Pt 1, 57–68. [Google Scholar] [CrossRef]
- Bernardi, P. Mitochondrial transport of cations: Channels, exchangers, and permeability transition. Physiol. Rev. 1999, 79, 1127–1155. [Google Scholar] [CrossRef] [PubMed]
- Gunter, T.E.; Gunter, K.K.; Sheu, S.S.; Gavin, C.E. Mitochondrial calcium transport: Physiological and pathological relevance. Am. J. Physiol. 1994, 267, C313–C339. [Google Scholar] [CrossRef]
- Vinnakota, K.C.; Bazil, J.N.; Van den Bergh, F.; Wiseman, R.W.; Beard, D.A. Feedback Regulation and Time Hierarchy of Oxidative Phosphorylation in Cardiac Mitochondria. Biophys. J. 2016, 110, 972–980. [Google Scholar] [CrossRef][Green Version]
- Wu, F.; Zhang, E.Y.; Zhang, J.; Bache, R.J.; Beard, D.A. Phosphate metabolite concentrations and ATP hydrolysis potential in normal and ischaemic hearts. J. Physiol. 2008, 586, 4193–4208. [Google Scholar] [CrossRef]
- Wu, F.; Jeneson, J.A.; Beard, D.A. Oxidative ATP synthesis in skeletal muscle is controlled by substrate feedback. Am. J. Physiol. Cell Physiol. 2007, 292, C115–C124. [Google Scholar] [CrossRef] [PubMed]
- Bose, S.; French, S.; Evans, F.J.; Joubert, F.; Balaban, R.S. Metabolic network control of oxidative phosphorylation: Multiple roles of inorganic phosphate. J. Biol. Chem. 2003, 278, 39155–39165. [Google Scholar] [CrossRef]
- Scholz, T.D.; Laughlin, M.R.; Balaban, R.S.; Kupriyanov, V.V.; Heineman, F.W. Effect of substrate on mitochondrial NADH, cytosolic redox state, and phosphorylated compounds in isolated hearts. Am. J. Physiol. 1995, 268, H82–H91. [Google Scholar] [CrossRef]
- LaNoue, K.F.; Bryla, J.; Williamson, J.R. Feedback interactions in the control of citric acid cycle activity in rat heart mitochondria. J. Biol. Chem. 1972, 247, 667–679. [Google Scholar] [CrossRef]
- LaNoue, K.; Nicklas, W.J.; Williamson, J.R. Control of citric acid cycle activity in rat heart mitochondria. J. Biol. Chem. 1970, 245, 102–111. [Google Scholar] [CrossRef]
- O’Donnell, J.M.; Doumen, C.; LaNoue, K.F.; White, L.T.; Yu, X.; Alpert, N.M.; Lewandowski, E.D. Dehydrogenase regulation of metabolite oxidation and efflux from mitochondria in intact hearts. Am. J. Physiol. 1998, 274, H467–H476. [Google Scholar] [CrossRef]
- Romani, A.M.P. Physiology and Pathology of Mitochondrial Dehydrogenases. In Secondary Metabolites—Sources and Applications; Ramasamy Vijayakumar, S.S.S.R., Ed.; IntechOpen: London, UK, 2018. [Google Scholar]
- Denton, R.M. Regulation of mitochondrial dehydrogenases by calcium ions. Biochim. Biophys. Acta 2009, 1787, 1309–1316. [Google Scholar] [CrossRef] [PubMed]
- McCormack, J.G.; Halestrap, A.P.; Denton, R.M. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol. Rev. 1990, 70, 391–425. [Google Scholar] [CrossRef]
- McCormack, J.G.; Denton, R.M. The role of Ca2+ in the regulation of intramitochondrial energy production in heart. Biomed. Biochim. Acta 1987, 46, S487–S492. [Google Scholar]
- Denton, R.M.; McCormack, J.G. The calcium sensitive dehydrogenases of vertebrate mitochondria. Cell Calcium 1986, 7, 377–386. [Google Scholar] [CrossRef]
- Denton, R.M.; McCormack, J.G.; Edgell, N.J. Role of calcium ions in the regulation of intramitochondrial metabolism. Effects of Na+, Mg2+ and ruthenium red on the Ca2+-stimulated oxidation of oxoglutarate and on pyruvate dehydrogenase activity in intact rat heart mitochondria. Biochem. J. 1980, 190, 107–117. [Google Scholar] [CrossRef] [PubMed]
- McCormack, J.G.; Denton, R.M. The effects of calcium ions and adenine nucleotides on the activity of pig heart 2-oxoglutarate dehydrogenase complex. Biochem. J. 1979, 180, 533–544. [Google Scholar] [CrossRef]
- Denton, R.M.; Richards, D.A.; Chin, J.G. Calcium ions and the regulation of NAD+-linked isocitrate dehydrogenase from the mitochondria of rat heart and other tissues. Biochem. J. 1978, 176, 899–906. [Google Scholar] [CrossRef]
- Williams, G.S.; Boyman, L.; Lederer, W.J. Mitochondrial calcium and the regulation of metabolism in the heart. J. Mol. Cell Cardiol. 2015, 78, 35–45. [Google Scholar] [CrossRef]
- Rossi, A.; Pizzo, P.; Filadi, R. Calcium, mitochondria and cell metabolism: A functional triangle in bioenergetics. Biochim. Biophys. Acta Mol. Cell Res. 2019, 1866, 1068–1078. [Google Scholar] [CrossRef]
- Finkel, T.; Menazza, S.; Holmstrom, K.M.; Parks, R.J.; Liu, J.; Sun, J.; Liu, J.; Pan, X.; Murphy, E. The ins and outs of mitochondrial calcium. Circ. Res. 2015, 116, 1810–1819. [Google Scholar] [CrossRef] [PubMed]
- McCormack, J.G.; Browne, H.M.; Dawes, N.J. Studies on mitochondrial Ca2+-transport and matrix Ca2+ using fura-2-loaded rat heart mitochondria. Biochim. Biophys. Acta 1989, 973, 420–427. [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][Green Version]
- Wan, B.; LaNoue, K.F.; Cheung, J.Y.; Scaduto, R.C., Jr. Regulation of citric acid cycle by calcium. J. Biol. Chem. 1989, 264, 13430–13439. [Google Scholar] [CrossRef]
- Vinnakota, K.C.; Singhal, A.; Van den Bergh, F.; Bagher-Oskouei, M.; Wiseman, R.W.; Beard, D.A. Open-Loop Control of Oxidative Phosphorylation in Skeletal and Cardiac Muscle Mitochondria by Ca2+. Biophys. J. 2016, 110, 954–961. [Google Scholar] [CrossRef]
- Glancy, B.; Balaban, R.S. Role of mitochondrial Ca2+ in the regulation of cellular energetics. Biochemistry 2012, 51, 2959–2973. [Google Scholar] [CrossRef]
- Griffiths, E.J.; Rutter, G.A. Mitochondrial calcium as a key regulator of mitochondrial ATP production in mammalian cells. Biochim. Biophys. Acta 2009, 1787, 1324–1333. [Google Scholar] [CrossRef]
- Balaban, R.S. The role of Ca2+ signaling in the coordination of mitochondrial ATP production with cardiac work. Biochim. Biophys. Acta 2009, 1787, 1334–1341. [Google Scholar] [CrossRef] [PubMed]
- Balaban, R.S.; Bose, S.; French, S.A.; Territo, P.R. Role of calcium in metabolic signaling between cardiac sarcoplasmic reticulum and mitochondria in vitro. Am. J. Physiol. Cell Physiol. 2003, 284, C285–C293. [Google Scholar] [CrossRef]
- 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] [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][Green Version]
- 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]
- Tewari, S.G.; Camara, A.K.; Stowe, D.F.; Dash, R.K. Computational analysis of Ca2+ dynamics in isolated cardiac mitochondria predicts two distinct modes of Ca2+ uptake. J. Physiol. 2014, 592, 1917–1930. [Google Scholar] [CrossRef]
- Dash, R.K.; Beard, D.A. Analysis of cardiac mitochondrial Na+-Ca2+ exchanger kinetics with a biophysical model of mitochondrial Ca2+ handling suggests a 3:1 stoichiometry. J. Physiol. 2008, 586, 3267–3285. [Google Scholar] [CrossRef] [PubMed]
- Williams, G.S.; Boyman, L.; Chikando, A.C.; Khairallah, R.J.; Lederer, W.J. Mitochondrial calcium uptake. Proc. Natl. Acad. Sci. USA 2013, 110, 10479–10486. [Google Scholar] [CrossRef]
- Glancy, B.; Willis, W.T.; Chess, D.J.; Balaban, R.S. Effect of calcium on the oxidative phosphorylation cascade in skeletal muscle mitochondria. Biochemistry 2013, 52, 2793–2809. [Google Scholar] [CrossRef]
- Eisner, D.A.; Caldwell, J.L.; Kistamás, K.; Trafford, A.W. Calcium and Excitation-Contraction Coupling in the Heart. Circ. Res. 2017, 121, 181–195. [Google Scholar] [CrossRef] [PubMed]
- Bers, D.M. Calcium cycling and signaling in cardiac myocytes. Annu. Rev. Physiol. 2008, 70, 23–49. [Google Scholar] [CrossRef]
- Singh, P.; Thomson, S.C. Metabolic Basis of Solute Transport. In Brenner and Rector’s The Kidney, 11st ed.; Elsevier: Amsterdam, The Netherlands, 2019. [Google Scholar]
- Forbes, J.M. Mitochondria;Power Players in Kidney Function? Trends Endocrinol. Metab. 2016, 27, 441–442. [Google Scholar] [CrossRef]
- Elia, M. Organ and Tissue Contribution to Metabolic Rate; Raven Press: New York, NY, USA, 1992. [Google Scholar]
- Pohjoismaki, J.L.; Goffart, S. The role of mitochondria in cardiac development and protection. Free Radic. Biol. Med. 2017, 106, 345–354. [Google Scholar] [CrossRef] [PubMed]
- Saks, V.; Dzeja, P.; Schlattner, U.; Vendelin, M.; Terzic, A.; Wallimann, T. Cardiac system bioenergetics: Metabolic basis of the Frank-Starling law. J. Physiol. 2006, 571, 253–273. [Google Scholar] [CrossRef]
- Hochachka, P.W.; McClelland, G.B. Cellular metabolic homeostasis during large-scale change in ATP turnover rates in muscles. J. Exp. Biol. 1997, 200, 381–386. [Google Scholar] [CrossRef]
- Soltoff, S.P. ATP and the regulation of renal cell function. Annu. Rev. Physiol. 1986, 48, 9–31. [Google Scholar] [CrossRef]
- Mandel, L.J. Metabolic substrates, cellular energy production, and the regulation of proximal tubular transport. Annu. Rev. Physiol. 1985, 47, 85–101. [Google Scholar] [CrossRef] [PubMed]
- Kiil, F. Renal energy metabolism and regulation of sodium reabsorption. Kidney Int. 1977, 11, 153–160. [Google Scholar] [CrossRef]
- Bankir, L.; Figueres, L.; Prot-Bertoye, C.; Bouby, N.; Crambert, G.; Pratt, J.H.; Houillier, P. Medullary and cortical thick ascending limb: Similarities and differences. Am. J. Physiol. Renal Physiol. 2020, 318, F422–F442. [Google Scholar] [CrossRef] [PubMed]
- Evans, L.C.; Cowley, A.W., Jr. Renal Medullary Circulation, 1st ed.; Morgan & Claypool Publishers: San Rafael, CA, USA, 1990; p. 104. [Google Scholar]
- Cheng, Y.; Song, H.; Pan, X.; Xue, H.; Wan, Y.; Wang, T.; Tian, Z.; Hou, E.; Lanza, I.R.; Liu, P.; et al. Urinary Metabolites Associated with Blood Pressure on a Low- or High-Sodium Diet. Theranostics 2018, 8, 1468–1480. [Google Scholar] [CrossRef] [PubMed]
- Cao, J.L.; Adaniya, S.M.; Cypress, M.W.; Suzuki, Y.; Kusakari, Y.; Jhun, B.S.; O-Uchi, J. Role of mitochondrial Ca(2+) homeostasis in cardiac muscles. Arch. Biochem. Biophys. 2019, 663, 276–287. [Google Scholar] [CrossRef]
- Lopaschuk, G.D. Targets for modulation of fatty acid oxidation in the heart. Curr. Opin. Investig. Drugs 2004, 5, 290–294. [Google Scholar] [PubMed]
- Fink, B.D.; Bai, F.; Yu, L.; Sivitz, W.I. Regulation of ATP production: Dependence on calcium concentration and respiratory state. Am. J. Physiol. Cell Physiol. 2017, 313, C146–C153. [Google Scholar] [CrossRef]
- Tarasov, A.I.; Griffiths, E.J.; Rutter, G.A. Regulation of ATP production by mitochondrial Ca(2+). Cell Calcium 2012, 52, 28–35. [Google Scholar] [CrossRef] [PubMed]
- Wollenman, L.C.; Vander Ploeg, M.R.; Miller, M.L.; Zhang, Y.; Bazil, J.N. The effect of respiration buffer composition on mitochondrial metabolism and function. PLoS ONE 2017, 12, e0187523. [Google Scholar] [CrossRef]
- Vinnakota, K.C.; Dash, R.K.; Beard, D.A. Stimulatory effects of calcium on respiration and NAD(P)H synthesis in intact rat heart mitochondria utilizing physiological substrates cannot explain respiratory control in vivo. J. Biol. Chem. 2011, 286, 30816–30822. [Google Scholar] [CrossRef]
- Panov, A.V.; Scaduto, R.C., Jr. Substrate specific effects of calcium on metabolism of rat heart mitochondria. Am. J. Physiol. 1996, 270, H1398–H1406. [Google Scholar] [CrossRef]
- Tomar, N.; Zhang, X.; Kandel, S.M.; Sadri, S.; Yang, C.; Liang, M.; Audi, S.H.; Cowley, A.W., Jr.; Dash, R.K. Substrate-dependent differential regulation of mitochondrial bioenergetics in the heart and kidney cortex and outer medulla. Biochim. Biophys. Acta Bioenerg. 2021, 1863, 148518. [Google Scholar] [CrossRef]
- Agarwal, B.; Camara, A.K.; Stowe, D.F.; Bosnjak, Z.J.; Dash, R.K. Enhanced charge-independent mitochondrial free Ca(2+) and attenuated ADP-induced NADH oxidation by isoflurane: Implications for cardioprotection. Biochim. Biophys. Acta 2012, 1817, 453–465. [Google Scholar] [CrossRef] [PubMed][Green Version]
- 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]
- Schoenmakers, T.J.; Visser, G.J.; Flik, G.; Theuvenet, A.P. CHELATOR: An improved method for computing metal ion concentrations in physiological solutions. Biotechniques 1992, 12, 870–874, 876–879. [Google Scholar]
- McKnight, S.L. On getting there from here. Science 2010, 330, 1338–1339. [Google Scholar] [CrossRef]
- Langman, C.B.; Cannata-Andía, J.B. Calcium in chronic kidney disease: Myths and realities. Introduction. Clin. J. Am. Soc. Nephrol. 2010, 5 (Suppl. 1), S1–S2. [Google Scholar] [CrossRef]
- Chiodini, I.; Bolland, M.J. Calcium supplementation in osteoporosis: Useful or harmful? Eur. J. Endocrinol. 2018, 178, D13–D25. [Google Scholar] [CrossRef]
- Forner, F.; Foster, L.J.; Campanaro, S.; Valle, G.; Mann, M. Quantitative proteomic comparison of rat mitochondria from muscle, heart, and liver. Mol. Cell Proteom. 2006, 5, 608–619. [Google Scholar] [CrossRef]
- Rossignol, R.; Letellier, T.; Malgat, M.; Rocher, C.; Mazat, J.P. Tissue variation in the control of oxidative phosphorylation: Implication for mitochondrial diseases. Biochem. J. 2000, 347 Pt 1, 45–53. [Google Scholar] [CrossRef]
- Shirley, M.K.; Arthurs, O.J.; Seunarine, K.K.; Cole, T.J.; Eaton, S.; Williams, J.E.; Clark, C.A.; Wells, J.C.K. Metabolic rate of major organs and tissues in young adult South Asian women. Eur. J. Clin. Nutr. 2019, 73, 1164–1171. [Google Scholar] [CrossRef] [PubMed]
- Goffart, S.; von Kleist-Retzow, J.-C.; Wiesner, R.J. Regulation of mitochondrial proliferation in the heart: Power-plant failure contributes to cardiac failure in hypertrophy. Cardiovasc. Res. 2004, 64, 198–207. [Google Scholar] [CrossRef] [PubMed]
- Boyman, L.; Chikando, A.C.; Williams, G.S.; Khairallah, R.J.; Kettlewell, S.; Ward, C.W.; Smith, G.L.; Kao, J.P.; Lederer, W.J. Calcium movement in cardiac mitochondria. Biophys. J. 2014, 107, 1289–1301. [Google Scholar] [CrossRef] [PubMed]
- Rossitto, G.; Maiolino, G.; Lerco, S.; Ceolotto, G.; Blackburn, G.; Mary, S.; Antonelli, G.; Berton, C.; Bisogni, V.; Cesari, M.; et al. High sodium intake, glomerular hyperfiltration, and protein catabolism in patients with essential hypertension. Cardiovasc. Res. 2021, 117, 1372–1381. [Google Scholar] [CrossRef]
- Stillman, I.E.; Brezis, M.; Heyman, S.N.; Epstein, F.H.; Spokes, K.; Rosen, S. Effects of salt depletion on the kidney: Changes in medullary oxygenation and thick ascending limb size. J. Am. Soc. Nephrol. 1994, 4, 1538–1545. [Google Scholar] [CrossRef] [PubMed]
- Friederich-Persson, M.; Thorn, E.; Hansell, P.; Nangaku, M.; Levin, M.; Palm, F. Kidney hypoxia, attributable to increased oxygen consumption, induces nephropathy independently of hyperglycemia and oxidative stress. Hypertension 2013, 62, 914–919. [Google Scholar] [CrossRef] [PubMed]
- Kunz, W.S. Different metabolic properties of mitochondrial oxidative phosphorylation in different cell types--important implications for mitochondrial cytopathies. Exp. Physiol. 2003, 88, 149–154. [Google Scholar] [CrossRef]
- Cortassa, S.; Aon, M.A.; Sollott, S.J. Control and Regulation of Substrate Selection in Cytoplasmic and Mitochondrial Catabolic Networks. A Systems Biology Analysis. Front. Physiol. 2019, 10, 201. [Google Scholar] [CrossRef]
- Hinkle, P.C.; Yu, M.L. The phosphorus/oxygen ratio of mitochondrial oxidative phosphorylation. J. Biol. Chem. 1979, 254, 2450–2455. [Google Scholar] [CrossRef]
- Hinkle, P.C. P/O ratios of mitochondrial oxidative phosphorylation. Biochim. Biophys. Acta 2005, 1706, 1–11. [Google Scholar] [CrossRef]
- Hinkle, P.C.; Kumar, M.A.; Resetar, A.; Harris, D.L. Mechanistic stoichiometry of mitochondrial oxidative phosphorylation. Biochemistry 1991, 30, 3576–3582. [Google Scholar] [CrossRef]
- Santo-Domingo, J.; Demaurex, N. Calcium uptake mechanisms of mitochondria. Biochim. Biophys. Acta 2010, 1797, 907–912. [Google Scholar] [CrossRef]
- Dash, R.K.; Qi, F.; Beard, D.A. A biophysically based mathematical model for the kinetics of mitochondrial calcium uniporter. Biophys. J. 2009, 96, 1318–1332. [Google Scholar] [CrossRef]
- Lehninger, A.L.; Reynafarje, B.; Vercesi, A.; Tew, W.P. Transport and accumulation of calcium in mitochondria. Ann. N. Y. Acad. Sci. 1978, 307, 160–176. [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] [PubMed]
- Pradhan, R.K.; Qi, F.; Beard, D.A.; Dash, R.K. Characterization of Mg2+ inhibition of mitochondrial Ca2+ uptake by a mechanistic model of mitochondrial Ca2+ uniporter. Biophys. J. 2011, 101, 2071–2081. [Google Scholar] [CrossRef] [PubMed]
- Crompton, M.; Kunzi, M.; Carafoli, E. The calcium-induced and sodium-induced effluxes of calcium from heart mitochondria. Evidence for a sodium-calcium carrier. Eur. J. Biochem. 1977, 79, 549–558. [Google Scholar] [CrossRef]
- Gunter, T.E.; Sheu, S.S. Characteristics and possible functions of mitochondrial Ca(2+) transport mechanisms. Biochim. Biophys. Acta 2009, 1787, 1291–1308. [Google Scholar] [CrossRef]
- Puskin, J.S.; Gunter, T.E.; Gunter, K.K.; Russell, P.R. Evidence for more than one Ca2+ transport mechanism in mitochondria. Biochemistry 1976, 15, 3834–3842. [Google Scholar] [CrossRef]
- Fiskum, G.; Lehninger, A.L. Regulated release of Ca2+ from respiring mitochondria by Ca2+/2H+ antiport. J. Biol. Chem. 1979, 254, 6236–6239. [Google Scholar] [CrossRef]
- 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]
- Korge, P.; Yang, L.; Yang, J.H.; Wang, Y.; Qu, Z.; Weiss, J.N. Protective role of transient pore openings in calcium handling by cardiac mitochondria. J. Biol. Chem. 2011, 286, 34851–34857. [Google Scholar] [CrossRef] [PubMed]
- Nicholls, D.G. The regulation of extramitochondrial free calcium ion concentration by rat liver mitochondria. Biochem. J. 1978, 176, 463–474. [Google Scholar] [CrossRef] [PubMed]
- Joseph, S.K.; Coll, K.E.; Cooper, R.H.; Marks, J.S.; Williamson, J.R. Mechanisms underlying calcium homeostasis in isolated hepatocytes. J. Biol. Chem. 1983, 258, 731–741. [Google Scholar] [CrossRef]
- Gherardi, G.; Monticelli, H.; Rizzuto, R.; Mammucari, C. The Mitochondrial Ca(2+) Uptake and the Fine-Tuning of Aerobic Metabolism. Front. Physiol. 2020, 11, 554904. [Google Scholar] [CrossRef]
- Szibor, M.; Gizatullina, Z.; Gainutdinov, T.; Endres, T.; Debska-Vielhaber, G.; Kunz, M.; Karavasili, N.; Hallmann, K.; Schreiber, F.; Bamberger, A.; et al. Cytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply. J. Biol. Chem. 2020, 295, 4383–4397. [Google Scholar] [CrossRef] [PubMed]
- Pan, X.; Liu, J.; Nguyen, T.; Liu, C.; Sun, J.; Teng, Y.; Fergusson, M.M.; Rovira, I.I.; Allen, M.; Springer, D.A.; et al. The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat. Cell Biol. 2013, 15, 1464–1472. [Google Scholar] [CrossRef]
- Holmstrom, K.M.; Pan, X.; Liu, J.C.; Menazza, S.; Liu, J.; Nguyen, T.T.; Pan, H.; Parks, R.J.; Anderson, S.; Noguchi, A.; et al. Assessment of cardiac function in mice lacking the mitochondrial calcium uniporter. J. Mol. Cell Cardiol. 2015, 85, 178–182. [Google Scholar] [CrossRef]
- Rasmussen, T.P.; Wu, Y.; Joiner, M.L.; Koval, O.M.; Wilson, N.R.; Luczak, E.D.; Wang, Q.; Chen, B.; Gao, Z.; Zhu, Z.; et al. Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart. Proc. Natl. Acad. Sci. USA 2015, 112, 9129–9134. [Google Scholar] [CrossRef]
- Hamilton, J.; Brustovetsky, T.; Rysted, J.E.; Lin, Z.; Usachev, Y.M.; Brustovetsky, N. Deletion of mitochondrial calcium uniporter incompletely inhibits calcium uptake and induction of the permeability transition pore in brain mitochondria. J. Biol. Chem. 2018, 293, 15652–15663. [Google Scholar] [CrossRef]
- Satrustegui, J.; Pardo, B.; Del Arco, A. Mitochondrial transporters as novel targets for intracellular calcium signaling. Physiol. Rev. 2007, 87, 29–67. [Google Scholar] [CrossRef]
- Luongo, T.S.; Lambert, J.P.; Yuan, A.; Zhang, X.; Gross, P.; Song, J.; Shanmughapriya, S.; Gao, E.; Jain, M.; Houser, S.R.; et al. The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition. Cell Rep. 2015, 12, 23–34. [Google Scholar] [CrossRef]
- Palmieri, L.; Pardo, B.; Lasorsa, F.M.; del Arco, A.; Kobayashi, K.; Iijima, M.; Runswick, M.J.; Walker, J.E.; Saheki, T.; Satrustegui, J.; et al. Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. EMBO J. 2001, 20, 5060–5069. [Google Scholar] [CrossRef] [PubMed]
- Satrustegui, J.; Contreras, L.; Ramos, M.; Marmol, P.; del Arco, A.; Saheki, T.; Pardo, B. Role of aralar, the mitochondrial transporter of aspartate-glutamate, in brain N-acetylaspartate formation and Ca(2+) signaling in neuronal mitochondria. J. Neurosci. Res. 2007, 85, 3359–3366. [Google Scholar] [CrossRef]
- Llorente-Folch, I.; Rueda, C.B.; Amigo, I.; del Arco, A.; Saheki, T.; Pardo, B.; Satrustegui, J. Calcium-regulation of mitochondrial respiration maintains ATP homeostasis and requires ARALAR/AGC1-malate aspartate shuttle in intact cortical neurons. J. Neurosci. 2013, 33, 13957–13971. [Google Scholar] [CrossRef]
- Gellerich, F.N.; Gizatullina, Z.; Arandarcikaite, O.; Jerzembek, D.; Vielhaber, S.; Seppet, E.; Striggow, F. Extramitochondrial Ca2+ in the nanomolar range regulates glutamate-dependent oxidative phosphorylation on demand. PLoS ONE 2009, 4, e8181. [Google Scholar] [CrossRef]
- LaNoue, K.F.; Williamson, J.R. Interrelationships between malate-aspartate shuttle and citric acid cycle in rat heart mitochondria. Metabolism 1971, 20, 119–140. [Google Scholar] [CrossRef]
- Williamson, J.R.; Safer, B.; LaNoue, K.F.; Smith, C.M.; Walajtys, E. Mitochondrial-cytosolic interactions in cardiac tissue: Role of the malate-aspartate cycle in the removal of glycolytic NADH from the cytosol. Symp. Soc. Exp. Biol. 1973, 27, 241–281. [Google Scholar]
- 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] [CrossRef]
- Carafoli, E.; Lehninger, A.L. A survey of the interaction of calcium ions with mitochondria from different tissues and species. Biochem. J. 1971, 122, 681–690. [Google Scholar] [CrossRef] [PubMed]
- Hansford, R.G.; Moreno-Sanchez, R.; Lewartowski, B. Activation of pyruvate dehydrogenase complex by Ca2+ in intact heart, cardiac myocytes, and cardiac mitochondria. Ann. N. Y. Acad. Sci. 1989, 573, 240–253. [Google Scholar] [CrossRef]
- Randle, P.J.; Denton, R.M.; Pask, H.T.; Severson, D.L. Calcium ions and the regulation of pyruvate dehydrogenase. Biochem. Soc. Symp. 1974, 75–88. [Google Scholar]
- Gellerich, F.N.; Gizatullina, Z.; Trumbeckaite, S.; Nguyen, H.P.; Pallas, T.; Arandarcikaite, O.; Vielhaber, S.; Seppet, E.; Striggow, F. The regulation of OXPHOS by extramitochondrial calcium. Biochim. Biophys. Acta 2010, 1797, 1018–1027. [Google Scholar] [CrossRef] [PubMed]
- Cole, E.S.; Lepp, C.A.; Holohan, P.D.; Fondy, T.P. Isolation and characterization of flavin-linked glycerol-3-phosphate dehydrogenase from rabbit skeletal muscle mitochondria and comparison with the enzyme from rabbit brain. J. Biol. Chem. 1978, 253, 7952–7959. [Google Scholar] [CrossRef]
- Rutter, G.A.; Denton, R.M. Regulation of NAD+-linked isocitrate dehydrogenase and 2-oxoglutarate dehydrogenase by Ca2+ ions within toluene-permeabilized rat heart mitochondria. Interactions with regulation by adenine nucleotides and NADH/NAD+ ratios. Biochem. J. 1988, 252, 181–189. [Google Scholar] [CrossRef] [PubMed]
- Rutter, G.A.; Denton, R.M. The binding of Ca2+ ions to pig heart NAD+-isocitrate dehydrogenase and the 2-oxoglutarate dehydrogenase complex. Biochem. J. 1989, 263, 453–462. [Google Scholar] [CrossRef] [PubMed]
- Contreras, L.; Gomez-Puertas, P.; Iijima, M.; Kobayashi, K.; Saheki, T.; Satrústegui, J. Ca2+ Activation kinetics of the two aspartate-glutamate mitochondrial carriers, aralar and citrin: Role in the heart malate-aspartate NADH shuttle. J. Biol. Chem. 2007, 282, 7098–7106. [Google Scholar] [CrossRef]
- Qi, F.; Chen, X.; Beard, D.A. Detailed kinetics and regulation of mammalian NAD-linked isocitrate dehydrogenase. Biochim. Biophys. Acta 2008, 1784, 1641–1651. [Google Scholar] [CrossRef]
- Contreras, L.; Drago, I.; Zampese, E.; Pozzan, T. Mitochondria: The calcium connection. Biochim. Biophys. Acta 2010, 1797, 607–618. [Google Scholar] [CrossRef]
- Nicholls, D.G.; Budd, S.L. Mitochondria and neuronal survival. Physiol. Rev. 2000, 80, 315–360. [Google Scholar] [CrossRef]
- Matsuzaki, S.; Szweda, L.I. Inhibition of complex I by Ca2+ reduces electron transport activity and the rate of superoxide anion production in cardiac submitochondrial particles. Biochemistry 2007, 46, 1350–1357. [Google Scholar] [CrossRef]
- Lai, J.C.; DiLorenzo, J.C.; Sheu, K.F. Pyruvate dehydrogenase complex is inhibited in calcium-loaded cerebrocortical mitochondria. Neurochem. Res. 1988, 13, 1043–1048. [Google Scholar] [CrossRef]
- Abou-Khalil, S.; Abou-Khalil, W.H.; Yunis, A.A. Inhibition of Ca2+ of oxidative phosphorylation in myeloid tumor mitochondria. Arch. Biochem. Biophys. 1981, 209, 460–464. [Google Scholar] [CrossRef]
- 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]
Substrate Code | Substrates * | Final Concentrations |
---|---|---|
PM | Pyruvate + Malate | 5 mM + 2.5 mM |
GM | Glutamate + Malate | 5 mM + 2.5 mM |
AM | Alpha-Ketoglutarate + Malate | 5 mM + 2.5 mM |
PCM | Palmitoyl-carnitine + Malate | 25 µM + 2.5 mM |
SUC + ROT | Succinate + Rotenone | 10 mM + 0.5 µM |
[Ca2+]total (µM) | [Ca2+]free (nM) |
---|---|
0 | 0 |
250 | 100 |
400 | 200 |
700 | 720 |
750 | 925 |
800 | 1230 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Zhang, X.; Tomar, N.; Kandel, S.M.; Audi, S.H.; Cowley, A.W., Jr.; Dash, R.K. Substrate- and Calcium-Dependent Differential Regulation of Mitochondrial Oxidative Phosphorylation and Energy Production in the Heart and Kidney. Cells 2022, 11, 131. https://doi.org/10.3390/cells11010131
Zhang X, Tomar N, Kandel SM, Audi SH, Cowley AW Jr., Dash RK. Substrate- and Calcium-Dependent Differential Regulation of Mitochondrial Oxidative Phosphorylation and Energy Production in the Heart and Kidney. Cells. 2022; 11(1):131. https://doi.org/10.3390/cells11010131
Chicago/Turabian StyleZhang, Xiao, Namrata Tomar, Sunil M. Kandel, Said H. Audi, Allen W. Cowley, Jr., and Ranjan K. Dash. 2022. "Substrate- and Calcium-Dependent Differential Regulation of Mitochondrial Oxidative Phosphorylation and Energy Production in the Heart and Kidney" Cells 11, no. 1: 131. https://doi.org/10.3390/cells11010131
APA StyleZhang, X., Tomar, N., Kandel, S. M., Audi, S. H., Cowley, A. W., Jr., & Dash, R. K. (2022). Substrate- and Calcium-Dependent Differential Regulation of Mitochondrial Oxidative Phosphorylation and Energy Production in the Heart and Kidney. Cells, 11(1), 131. https://doi.org/10.3390/cells11010131