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

Open AccessPublished:July 24, 2020DOI:https://doi.org/10.1074/jbc.L120.013975
      Szibor et al. (
      • Szibor 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.
      ) 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) (
      • McCormack J.G.
      • Halestrap A.P.
      • Denton R.M.
      Role of calcium ions in regulation of mammalian intramitochondrial metabolism.
      ), but Szibor et al. (
      • Szibor 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.
      ) 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 (
      • McCormack 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.
      ,
      • Hansford R.G.
      • Castro F.
      Role of Ca2+ in pyruvate dehydrogenase interconversion in brain mitochondria and synaptosomes.
      ,
      • Griffiths E.J.
      • Rutter G.A.
      Mitochondrial calcium as a key regulator of mitochondrial ATP production in mammalian cells.
      ).
      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 (
      • McCormack J.G.
      • Halestrap A.P.
      • Denton R.M.
      Role of calcium ions in regulation of mammalian intramitochondrial metabolism.
      ). 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 (
      • McCormack J.G.
      • Halestrap A.P.
      • Denton R.M.
      Role of calcium ions in regulation of mammalian intramitochondrial metabolism.
      ). Indeed, blockade of the mitochondrial Ca2+ uniporter (MCU) using ruthenium red decreases ATP/ADP ratios in stimulated hearts (
      • Unitt 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.
      ), consistent with reduced exercise tolerance in MCU-null mice (
      • Pan 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.
      ), even though core intrinsic mechanisms are retained. Furthermore,mitochondrial Ca2+ influx is not completely suppressed by MCU deletion (
      • Pan 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.
      ).

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