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000151065 1001_ $$00000-0003-4029-160X$$aSzibor, Marten$$b0
000151065 245__ $$aCytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply
000151065 260__ $$aBethesda, MD.$$bAmerican Soc. for Biochemistry and Molecular Biology8772$$c2020
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000151065 520__ $$aMitochondrial oxidative phosphorylation (OXPHOS) and cellular workload are tightly balanced by the key cellular regulator, calcium (Ca2+). Current models assume that cytosolic Ca2+ regulates workload and that mitochondrial Ca2+ uptake precedes activation of matrix dehydrogenases, thereby matching OXPHOS substrate supply to ATP demand. Surprisingly, knockout (KO) of the mitochondrial Ca2+ uniporter (MCU) in mice results in only minimal phenotypic changes and does not alter OXPHOS. This implies that adaptive activation of mitochondrial dehydrogenases by intramitochondrial Ca2+ cannot be the exclusive mechanism for OXPHOS control. We hypothesized that cytosolic Ca2+, but not mitochondrial matrix Ca2+, may adapt OXPHOS to workload by adjusting the rate of pyruvate supply from the cytosol to the mitochondria. Here, we studied the role of malate-aspartate shuttle (MAS)-dependent substrate supply in OXPHOS responses to changing Ca2+ concentrations in isolated brain and heart mitochondria, synaptosomes, fibroblasts, and thymocytes from WT and MCU KO mice and the isolated working rat heart. Our results indicate that extramitochondrial Ca2+ controls up to 85% of maximal pyruvate-driven OXPHOS rates, mediated by the activity of the complete MAS, and that intramitochondrial Ca2+ accounts for the remaining 15%. Of note, the complete MAS, as applied here, included besides its classical NADH oxidation reaction the generation of cytosolic pyruvate. Part of this largely neglected mechanism has previously been described as the “mitochondrial gas pedal.” Its implementation into OXPHOS control models integrates seemingly contradictory results and warrants a critical reappraisal of metabolic control mechanisms in health and disease. 
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000151065 542__ $$2Crossref$$i2020-11-13$$uhttp://creativecommons.org/licenses/by/4.0/
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000151065 650_2 $$2MeSH$$aAnimals
000151065 650_2 $$2MeSH$$aAspartic Acid: metabolism
000151065 650_2 $$2MeSH$$aBrain: metabolism
000151065 650_2 $$2MeSH$$aCalcium: metabolism
000151065 650_2 $$2MeSH$$aCalcium Channels: deficiency
000151065 650_2 $$2MeSH$$aCalcium Channels: genetics
000151065 650_2 $$2MeSH$$aCytosol: metabolism
000151065 650_2 $$2MeSH$$aGlutamic Acid: chemistry
000151065 650_2 $$2MeSH$$aGlutamic Acid: metabolism
000151065 650_2 $$2MeSH$$aHeart: physiology
000151065 650_2 $$2MeSH$$aMalates: chemistry
000151065 650_2 $$2MeSH$$aMalates: metabolism
000151065 650_2 $$2MeSH$$aMembrane Potential, Mitochondrial
000151065 650_2 $$2MeSH$$aMice
000151065 650_2 $$2MeSH$$aMice, Inbred C57BL
000151065 650_2 $$2MeSH$$aMice, Knockout
000151065 650_2 $$2MeSH$$aMitochondria: metabolism
000151065 650_2 $$2MeSH$$aMyocardium: metabolism
000151065 650_2 $$2MeSH$$aOxidative Phosphorylation
000151065 650_2 $$2MeSH$$aPyruvic Acid: metabolism
000151065 650_2 $$2MeSH$$aRats
000151065 650_2 $$2MeSH$$aSubstrate Specificity
000151065 650_2 $$2MeSH$$aSynaptosomes: metabolism
000151065 7001_ $$aGizatullina, Zemfira$$b1
000151065 7001_ $$00000-0003-1723-1780$$aGainutdinov, Timur$$b2
000151065 7001_ $$00000-0003-4263-2922$$aEndres, Thomas$$b3
000151065 7001_ $$0P:(DE-HGF)0$$aDebska-Vielhaber, Grazyna$$b4
000151065 7001_ $$aKunz, Matthias$$b5
000151065 7001_ $$aKaravasili, Niki$$b6
000151065 7001_ $$aHallmann, Kerstin$$b7
000151065 7001_ $$0P:(DE-2719)9000986$$aSchreiber, Frank$$b8$$udzne
000151065 7001_ $$aBamberger, Alexandra$$b9
000151065 7001_ $$00000-0001-9698-4830$$aSchwarzer, Michael$$b10
000151065 7001_ $$aDoenst, Torsten$$b11
000151065 7001_ $$0P:(DE-2719)2260426$$aHeinze, Hans-Jochen$$b12$$udzne
000151065 7001_ $$aLessmann, Volkmar$$b13
000151065 7001_ $$0P:(DE-2719)2000035$$aVielhaber, Stefan$$b14$$udzne
000151065 7001_ $$00000-0003-1113-3493$$aKunz, Wolfram S.$$b15
000151065 7001_ $$00000-0002-6550-4555$$aGellerich, Frank N.$$b16
000151065 77318 $$2Crossref$$3journal-article$$a10.1074/jbc.ra119.011902$$bElsevier BV$$d2020-04-01$$n14$$p4383-4397$$tJournal of Biological Chemistry$$v295$$x0021-9258$$y2020
000151065 773__ $$0PERI:(DE-600)1474604-9$$a10.1074/jbc.RA119.011902$$gVol. 295, no. 14, p. 4383 - 4397$$n14$$p4383-4397$$tThe journal of biological chemistry$$v295$$x0021-9258$$y2020
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000151065 9131_ $$0G:(DE-HGF)POF3-344$$1G:(DE-HGF)POF3-340$$2G:(DE-HGF)POF3-300$$aDE-HGF$$bForschungsbereich Gesundheit$$lErkrankungen des Nervensystems$$vClinical and Health Care Research$$x0
000151065 9141_ $$y2020
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