Cytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply
| Autor: | Thomas Endres, Stefan Vielhaber, Kerstin Hallmann, Niki Karavasili, Marten Szibor, Frank Schreiber, T. M. Gainutdinov, Volkmar Lessmann, Michael Schwarzer, Zemfira Gizatullina, Torsten Doenst, Matthias Kunz, Wolfram S. Kunz, Grazyna Debska-Vielhaber, Frank N. Gellerich, Alexandra Bamberger, Hans-Jochen Heinze |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Bioenergetics metabolism [Pyruvic Acid] Respiratory chain Mitochondrion bioenergetics Biochemistry Oxidative Phosphorylation Substrate Specificity Mice metabolism [Calcium] physiology [Heart] Membrane Potential Mitochondrial Mice Knockout Chemistry chemistry [Glutamic Acid] cytosolic calcium Cell biology mitochondria chemistry [Malates] synaptosomes mitochondrial calcium uniporter mouse OXPHOS control isolated working rat heart malate-aspartate shuttle thymocytes fibroblasts respiratory chain calcium Mitochondrial matrix genetics [Calcium Channels] Malate-aspartate shuttle deficiency [Calcium Channels] Oxidative phosphorylation 03 medical and health sciences Animals Editors' Picks ddc:610 metabolism [Synaptosomes] Uniporter Molecular Biology 030102 biochemistry & molecular biology metabolism [Glutamic Acid] Cell Biology metabolism [Malates] metabolism [Mitochondria] metabolism [Aspartic Acid] Rats Mice Inbred C57BL Cytosol 030104 developmental biology metabolism [Brain] metabolism [Cytosol] metabolism [Myocardium] |
| Zdroj: | The journal of biological chemistry 295(14), 4383-4397 (2020). doi:10.1074/jbc.RA119.011902 The journal of biological chemistry, 295(14):4383-4397 The Journal of Biological Chemistry |
| DOI: | 10.1074/jbc.RA119.011902 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|