Cytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply

  1. Szibor, Marten ORCID logo
  2. Gizatullina, Zemfira
  3. Gainutdinov, Timur ORCID logo
  4. Endres, Thomas ORCID logo
  5. Debska-Vielhaber, Grazyna
  6. Kunz, Matthias
  7. Karavasili, Niki
  8. Hallmann, Kerstin
  9. Schreiber, Frank
  10. Bamberger, Alexandra
  11. Schwarzer, Michael ORCID logo
  12. Doenst, Torsten
  13. Heinze, Hans-Jochen
  14. Lessmann, Volkmar
  15. Vielhaber, Stefan
  16. Kunz, Wolfram ORCID logo
  17. Gellerich, Frank ORCID logo

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WeightNameValue
1000 Titel
  • Cytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply
1000 Autor/in
  1. Szibor, Marten |
  2. Gizatullina, Zemfira |
  3. Gainutdinov, Timur |
  4. Endres, Thomas |
  5. Debska-Vielhaber, Grazyna |
  6. Kunz, Matthias |
  7. Karavasili, Niki |
  8. Hallmann, Kerstin |
  9. Schreiber, Frank |
  10. Bamberger, Alexandra |
  11. Schwarzer, Michael |
  12. Doenst, Torsten |
  13. Heinze, Hans-Jochen |
  14. Lessmann, Volkmar |
  15. Vielhaber, Stefan |
  16. Kunz, Wolfram |
  17. Gellerich, Frank |
1000 Erscheinungsjahr 2021
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2021-01-04
1000 Erschienen in
1000 Quellenangabe
  • 295(14):4383-4397
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2020
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1074/jbc.RA119.011902 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135991/ |
1000 Ergänzendes Material
  • https://www.sciencedirect.com/science/article/pii/S0021925817487060#sec1 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • 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.
1000 Sacherschließung
lokal mitochondria
lokal synaptosomes
lokal mitochondrial calcium uniporter
lokal cytosolic calcium
lokal mouse
lokal OXPHOS control
lokal isolated working rat heart
lokal malate-aspartate shuttle
lokal thymocytes
lokal fibroblasts
lokal bioenergetics
lokal respiratory chain
lokal calcium
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://orcid.org/0000-0003-4029-160X|https://frl.publisso.de/adhoc/uri/R2l6YXR1bGxpbmEsIFplbWZpcmE=|https://orcid.org/0000-0003-1723-1780|https://orcid.org/0000-0003-4263-2922|https://frl.publisso.de/adhoc/uri/RGVic2thLVZpZWxoYWJlciwgR3JhenluYQ==|https://frl.publisso.de/adhoc/uri/S3VueiwgTWF0dGhpYXM=|https://frl.publisso.de/adhoc/uri/S2FyYXZhc2lsaSwgTmlraQ==|https://frl.publisso.de/adhoc/uri/SGFsbG1hbm4sIEtlcnN0aW4=|https://frl.publisso.de/adhoc/uri/U2NocmVpYmVyLCBGcmFuaw==|https://frl.publisso.de/adhoc/uri/QmFtYmVyZ2VyLCBBbGV4YW5kcmE=|https://orcid.org/0000-0001-9698-4830|https://frl.publisso.de/adhoc/uri/RG9lbnN0LCBUb3JzdGVu|https://frl.publisso.de/adhoc/uri/SGVpbnplLCBIYW5zLUpvY2hlbg==|https://frl.publisso.de/adhoc/uri/TGVzc21hbm4sIFZvbGttYXI=|https://frl.publisso.de/adhoc/uri/VmllbGhhYmVyLCBTdGVmYW4=|https://orcid.org/0000-0003-1113-3493|https://orcid.org/0000-0002-6550-4555
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1000 Erstellt am 2021-06-25T10:29:05.368+0200
1000 Erstellt von 242
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1000 Zuletzt bearbeitet Thu Sep 09 12:28:53 CEST 2021
1000 Objekt bearb. Thu Sep 09 12:28:41 CEST 2021
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1000 Oai Id
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