Home > Publications Database > Cytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply > print

001     151065
005     20230915093948.0
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024 7 _ |a 10.1074/jbc.RA119.011902
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024 7 _ |a 0006-3347
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024 7 _ |a 0021-9258
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041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Szibor, Marten
|0 0000-0003-4029-160X
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245 _ _ |a Cytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply
260 _ _ |a Bethesda, MD.
|c 2020
|b American Soc. for Biochemistry and Molecular Biology8772
264 _ 1 |3 online
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|c 2020-02-24
264 _ 1 |3 print
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|b American Society for Biochemistry & Molecular Biology (ASBMB)
|c 2020-04-03
336 7 _ |a article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a Mitochondrial 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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542 _ _ |i 2020-04-01
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|u https://www.elsevier.com/tdm/userlicense/1.0/
542 _ _ |i 2020-11-13
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|u http://creativecommons.org/licenses/by/4.0/
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650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Aspartic Acid: metabolism
|2 MeSH
650 _ 2 |a Brain: metabolism
|2 MeSH
650 _ 2 |a Calcium: metabolism
|2 MeSH
650 _ 2 |a Calcium Channels: deficiency
|2 MeSH
650 _ 2 |a Calcium Channels: genetics
|2 MeSH
650 _ 2 |a Cytosol: metabolism
|2 MeSH
650 _ 2 |a Glutamic Acid: chemistry
|2 MeSH
650 _ 2 |a Glutamic Acid: metabolism
|2 MeSH
650 _ 2 |a Heart: physiology
|2 MeSH
650 _ 2 |a Malates: chemistry
|2 MeSH
650 _ 2 |a Malates: metabolism
|2 MeSH
650 _ 2 |a Membrane Potential, Mitochondrial
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Mice, Knockout
|2 MeSH
650 _ 2 |a Mitochondria: metabolism
|2 MeSH
650 _ 2 |a Myocardium: metabolism
|2 MeSH
650 _ 2 |a Oxidative Phosphorylation
|2 MeSH
650 _ 2 |a Pyruvic Acid: metabolism
|2 MeSH
650 _ 2 |a Rats
|2 MeSH
650 _ 2 |a Substrate Specificity
|2 MeSH
650 _ 2 |a Synaptosomes: metabolism
|2 MeSH
700 1 _ |a Gizatullina, Zemfira
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700 1 _ |a Gainutdinov, Timur
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700 1 _ |a Endres, Thomas
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700 1 _ |a Debska-Vielhaber, Grazyna
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700 1 _ |a Kunz, Matthias
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700 1 _ |a Karavasili, Niki
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700 1 _ |a Hallmann, Kerstin
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700 1 _ |a Schreiber, Frank
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700 1 _ |a Bamberger, Alexandra
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700 1 _ |a Schwarzer, Michael
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700 1 _ |a Doenst, Torsten
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700 1 _ |a Heinze, Hans-Jochen
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700 1 _ |a Lessmann, Volkmar
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700 1 _ |a Vielhaber, Stefan
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700 1 _ |a Kunz, Wolfram S.
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700 1 _ |a Gellerich, Frank N.
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773 _ _ |a 10.1074/jbc.RA119.011902
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