Journal Article

DZNE-2020-01050

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Cytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply

Szibor, M. ; Gizatullina, Z. ; Gainutdinov, T. ; Endres, T. ; Debska-Vielhaber, G. ; Kunz, M. ; Karavasili, N. ; Hallmann, K. ; Schreiber, F.DZNE* ; Bamberger, A. ; Schwarzer, M. ; Doenst, T. ; Heinze, H.-J.DZNE* ; Lessmann, V. ; Vielhaber, S.DZNE* ; Kunz, W. S. ; Gellerich, F. N.

2020
American Soc. for Biochemistry and Molecular Biology8772 Bethesda, MD.

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Please use a persistent id in citations: doi:10.1074/jbc.RA119.011902

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.

Keyword(s): Animals (MeSH) ; Aspartic Acid: metabolism (MeSH) ; Brain: metabolism (MeSH) ; Calcium: metabolism (MeSH) ; Calcium Channels: deficiency (MeSH) ; Calcium Channels: genetics (MeSH) ; Cytosol: metabolism (MeSH) ; Glutamic Acid: chemistry (MeSH) ; Glutamic Acid: metabolism (MeSH) ; Heart: physiology (MeSH) ; Malates: chemistry (MeSH) ; Malates: metabolism (MeSH) ; Membrane Potential, Mitochondrial (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mice, Knockout (MeSH) ; Mitochondria: metabolism (MeSH) ; Myocardium: metabolism (MeSH) ; Oxidative Phosphorylation (MeSH) ; Pyruvic Acid: metabolism (MeSH) ; Rats (MeSH) ; Substrate Specificity (MeSH) ; Synaptosomes: metabolism (MeSH)

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Contributing Institute(s):

1. Magdeburg Pre 2020 (Magdeburg Pre 2020)
2. U Clinical Researchers - Magdeburg (U Clinical Researchers - Magdeburg)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2020

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; JCR ; PubMed Central ; SCOPUS ; Web of Science Core Collection

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