The roles of cytosolic and intramitochondrial Ca2+ and the mitochondrial Ca2+-uniporter (MCU) in the stimulation of mammalian oxidative phosphorylation

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Szibor et al. (1Szibor M. Gizatullina Z. Gainutdinov T. Endres T. Debska-Vielhaber G. Kunz M. Karavasili N. Hallmann K. Schreiber F. Bamberger A. Schwarzer M. Doenst T. Heinze H.J. Lessmann V. Vielhaber S. et al.Cytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply.J. Biol. Chem. 2020; 295 (32094224): 4383-439710.1074/jbc.RA119.011902Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar) concluded that mitochondrial pyruvate oxidation is regulated primarily by cytosolic Ca2+ ([Ca2+]cyt) activation of the malate-aspartate shuttle, rather than by mitochondrial Ca2+ ([Ca2+]mit) activation of intramitochondrial dehydrogenases. Pyruvate dehydrogenase (PDH) activity largely reflects the ratio of active nonphosphorylated PDH to inactive phosphorylated PDH (PDHP) (2McCormack J.G. Halestrap A.P. Denton R.M. Role of calcium ions in regulation of mammalian intramitochondrial metabolism.Physiol. Rev. 1990; 70 (2157230): 391-42510.1152/physrev.1990.70.2.391Crossref PubMed Scopus (1111) Google Scholar), but Szibor et al. (1Szibor M. Gizatullina Z. Gainutdinov T. Endres T. Debska-Vielhaber G. Kunz M. Karavasili N. Hallmann K. Schreiber F. Bamberger A. Schwarzer M. Doenst T. Heinze H.J. Lessmann V. Vielhaber S. et al.Cytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply.J. Biol. Chem. 2020; 295 (32094224): 4383-439710.1074/jbc.RA119.011902Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar) did not measure PDH/PDHP ratios. Moreover, their studies used unphysiological conditions with isolated mitochondria (saturating ADP); with synaptosomes, thymocytes, and fibroblasts (uncoupler and high pyruvate); and with perfused hearts (high pyruvate). These conditions likely suppress ATP-linked PDH kinase activity (inhibited by ADP and pyruvate), resulting in very high PDH/PDHP ratios. This severely limits any potential activation of PDH by the [Ca2+]mit-stimulated PDHP phosphatase, inevitably delivering the results obtained. Under more physiological conditions, where PDH/PDHP ratios are lower, many studies have shown that [Ca2+]mit is a key activator of pyruvate oxidation (3McCormack J.G. Edgell N.J. Denton R.M. Studies on the interactions of Ca2+ and pyruvate in the regulation of rat heart pyruvate dehydrogenase activity: effects of starvation and diabetes.Biochem. J. 1982; 202 (7092823): 419-42710.1042/bj2020419Crossref PubMed Scopus (19) Google Scholar, 4Hansford R.G. Castro F. Role of Ca2+ in pyruvate dehydrogenase interconversion in brain mitochondria and synaptosomes.Biochem. J. 1985; 227 (2581558): 129-13610.1042/bj2270129Crossref PubMed Scopus (71) Google Scholar, 5Griffiths E.J. Rutter G.A. Mitochondrial calcium as a key regulator of mitochondrial ATP production in mammalian cells.Biochim. Biophys. Acta. 2009; 1787 (19366607): 1324-133310.1016/j.bbabio.2009.01.019Crossref PubMed Scopus (211) Google Scholar). We suggest that stimulation of the malate-aspartate shuttle by [Ca2+]cyt (increasing mitochondrial oxidation of cytoplasmic NADH) complements regulation of intramitochondrial dehydrogenases by [Ca2+]mit (2McCormack J.G. Halestrap A.P. Denton R.M. Role of calcium ions in regulation of mammalian intramitochondrial metabolism.Physiol. Rev. 1990; 70 (2157230): 391-42510.1152/physrev.1990.70.2.391Crossref PubMed Scopus (1111) Google Scholar). The latter may be regarded as an evolutionary refinement of “intrinsic” mechanisms (also present in lower organisms) increasing ATP production without lowering ATP/ADP ratios (2McCormack J.G. Halestrap A.P. Denton R.M. Role of calcium ions in regulation of mammalian intramitochondrial metabolism.Physiol. Rev. 1990; 70 (2157230): 391-42510.1152/physrev.1990.70.2.391Crossref PubMed Scopus (1111) Google Scholar). Indeed, blockade of the mitochondrial Ca2+ uniporter (MCU) using ruthenium red decreases ATP/ADP ratios in stimulated hearts (6Unitt J.F. McCormack J.G. Reid D. MacLachlan L.K. England P.J. Direct evidence for a role of intramitochondrial Ca2+ in the regulation of oxidative phosphorylation in the stimulated rat heart studies using 31P n.m.r. and ruthenium red.Biochem. J. 1989; 262 (2479373): 293-30110.1042/bj2620293Crossref PubMed Scopus (59) Google Scholar), consistent with reduced exercise tolerance in MCU-null mice (7Pan X. Liu J. Nguyen T. Liu C. Sun J. Teng Y. Fergusson M.M. Rovira I.I. Allen M. Springer D.A. Aponte A.M. Gucek M. Balaban R.S. Murphy E. Finkel T. The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter.Nat. Cell Biol. 2013; 15 (24212091): 1464-147210.1038/ncb2868Crossref PubMed Scopus (396) Google Scholar), even though core intrinsic mechanisms are retained. Furthermore,mitochondrial Ca2+ influx is not completely suppressed by MCU deletion (7Pan X. Liu J. Nguyen T. Liu C. Sun J. Teng Y. Fergusson M.M. Rovira I.I. Allen M. Springer D.A. Aponte A.M. Gucek M. Balaban R.S. Murphy E. Finkel T. The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter.Nat. Cell Biol. 2013; 15 (24212091): 1464-147210.1038/ncb2868Crossref PubMed Scopus (396) Google Scholar). Reply to Rutter et al.: The roles of cytosolic and intramitochondrial Ca2+ and the mitochondrial Ca2+-uniporter (MCU) in the stimulation of mammalian oxidative phosphorylationJournal of Biological ChemistryVol. 295Issue 30PreviewEach model used in the work referred to by Rutter et al. (1) addressed certain aspects of mitochondrial biology, and together, they fully support the conclusions made. Please note that we describe Ca2+-mediated regulation of oxidative phosphorylation (OXPHOS) fluxes (2, 3) and do not question Ca2+-responsiveness of pyruvate dehydrogenase en-zyme activity (4). To address concerns such as those raised by Rutter et al. (1), we studied glutamate/malate-dependent OXPHOS in the absence of exogenous pyruvate in mitochondria, omitted pyruvate from cell experiments, and implemented the working rat heart model perfused by Krebs–Henseleit (glucose) buffer. Full-Text PDF Open Access

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