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@ARTICLE{Szibor:151065,
      author       = {Szibor, Marten and Gizatullina, Zemfira and Gainutdinov,
                      Timur and Endres, Thomas and Debska-Vielhaber, Grazyna and
                      Kunz, Matthias and Karavasili, Niki and Hallmann, Kerstin
                      and Schreiber, Frank and Bamberger, Alexandra and Schwarzer,
                      Michael and Doenst, Torsten and Heinze, Hans-Jochen and
                      Lessmann, Volkmar and Vielhaber, Stefan and Kunz, Wolfram S.
                      and Gellerich, Frank N.},
      title        = {{C}ytosolic, but not matrix, calcium is essential for
                      adjustment of mitochondrial pyruvate supply},
      journal      = {The journal of biological chemistry},
      volume       = {295},
      number       = {14},
      issn         = {0021-9258},
      address      = {Bethesda, MD.},
      publisher    = {American Soc. for Biochemistry and Molecular Biology8772},
      reportid     = {DZNE-2020-01050},
      pages        = {4383-4397},
      year         = {2020},
      abstract     = {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.},
      keywords     = {Animals / Aspartic Acid: metabolism / Brain: metabolism /
                      Calcium: metabolism / Calcium Channels: deficiency / Calcium
                      Channels: genetics / Cytosol: metabolism / Glutamic Acid:
                      chemistry / Glutamic Acid: metabolism / Heart: physiology /
                      Malates: chemistry / Malates: metabolism / Membrane
                      Potential, Mitochondrial / Mice / Mice, Inbred C57BL / Mice,
                      Knockout / Mitochondria: metabolism / Myocardium: metabolism
                      / Oxidative Phosphorylation / Pyruvic Acid: metabolism /
                      Rats / Substrate Specificity / Synaptosomes: metabolism},
      cin          = {Magdeburg Pre 2020 / U Clinical Researchers - Magdeburg},
      ddc          = {610},
      cid          = {I:(DE-2719)6000015 / I:(DE-2719)7000000},
      pnm          = {344 - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC7135991},
      pubmed       = {pmid:32094224},
      doi          = {10.1074/jbc.RA119.011902},
      url          = {https://pub.dzne.de/record/151065},
}