TY  - JOUR
AU  - Szibor, Marten
AU  - Gizatullina, Zemfira
AU  - Gainutdinov, Timur
AU  - Endres, Thomas
AU  - Debska-Vielhaber, Grazyna
AU  - Kunz, Matthias
AU  - Karavasili, Niki
AU  - Hallmann, Kerstin
AU  - Schreiber, Frank
AU  - Bamberger, Alexandra
AU  - Schwarzer, Michael
AU  - Doenst, Torsten
AU  - Heinze, Hans-Jochen
AU  - Lessmann, Volkmar
AU  - Vielhaber, Stefan
AU  - Kunz, Wolfram S.
AU  - Gellerich, Frank N.
TI  - Cytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply
JO  - The journal of biological chemistry
VL  - 295
IS  - 14
SN  - 0021-9258
CY  - Bethesda, MD.
PB  - American Soc. for Biochemistry and Molecular Biology8772
M1  - DZNE-2020-01050
SP  - 4383-4397
PY  - 2020
AB  - 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
KW  - Animals
KW  - Aspartic Acid: metabolism
KW  - Brain: metabolism
KW  - Calcium: metabolism
KW  - Calcium Channels: deficiency
KW  - Calcium Channels: genetics
KW  - Cytosol: metabolism
KW  - Glutamic Acid: chemistry
KW  - Glutamic Acid: metabolism
KW  - Heart: physiology
KW  - Malates: chemistry
KW  - Malates: metabolism
KW  - Membrane Potential, Mitochondrial
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mice, Knockout
KW  - Mitochondria: metabolism
KW  - Myocardium: metabolism
KW  - Oxidative Phosphorylation
KW  - Pyruvic Acid: metabolism
KW  - Rats
KW  - Substrate Specificity
KW  - Synaptosomes: metabolism
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC7135991
C6  - pmid:32094224
DO  - DOI:10.1074/jbc.RA119.011902
UR  - https://pub.dzne.de/record/151065
ER  -