Szibor 2020 J Biol Chem

Szibor Marten, Gizatullina Zemfira, Gainutdinov Timur, Endres Thomas, Debska-Vielhaber Grazyna, Kunz Matthias, Karavasili Niki, Hallmann Kerstin, Schreiber Frank, Bamberger Alexandra, Schwarzer Michael, Doenst Torsten, Heinze Hans-Jochen, Leßmann Volkmar, Vielhaber Stefan, Kunz Wolfram S, Gellerich Frank Norbert (2020) Cytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply. J Biol Chem 295:4383-97.

» PMID: 32094224 Open Access

Szibor Marten, Gizatullina Zemfira, Gainutdinov Timur, Endres Thomas, Debska-Vielhaber Grazyna, Kunz Matthias, Karavasili Niki, Hallmann Kerstin, Schreiber Frank, Bamberger Alexandra, Schwarzer Michael, Doenst Torsten, Heinze Hans-Jochen, Leßmann Volkmar, Vielhaber Stefan, Kunz Wolfram S, Gellerich Frank Norbert (2020) J Biol Chem

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, knock-out (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 on OXPHOS responses to changing Ca²⁺ concentrations in isolated brain and heart mitochondria, synaptosomes, fibroblasts, and thymocytes from wild-type (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.

Published under license by The American Society for Biochemistry and Molecular Biology, Inc. • Keywords: Bioenergetics, Calcium, Malate-aspartate shuttle, Mitochondria, Mitochondrial calcium uniporter, Mouse, Respiratory chain • Bioblast editor: Plangger M • O2k-Network Lab: DE Jena Szibor M, FI Helsinki Jacobs HT, DE Magdeburg Gellerich FN, DE Magdeburg Debska-Vielhaber G

Labels: MiParea: Respiration, Genetic knockout;overexpression 

Organism: Mouse  Tissue;cell: Nervous system  Preparation: Isolated mitochondria, Intact cells  Enzyme: Inner mt-membrane transporter  Regulation: Calcium  Coupling state: LEAK, OXPHOS  Pathway: N, S, Gp, CIV, NS, ROX  HRR: Oxygraph-2k 

Labels, 2020-03