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      Mitochondrial pyruvate and fatty acid flux modulate MICU1-dependent control of MCU activity

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          Abstract

          The tricarboxylic acid (TCA) cycle converts the end products of glycolysis and fatty acid β-oxidation into the reducing equivalents NADH and FADH 2. Although mitochondrial matrix uptake of Ca 2+ enhances ATP production, it remains unclear whether deprivation of mitochondrial TCA substrates alters mitochondrial Ca 2+ flux. We investigated the effect of TCA cycle substrates on MCU-mediated mitochondrial matrix uptake of Ca 2+, mitochondrial bioenergetics, and autophagic flux. Inhibition of glycolysis, mitochondrial pyruvate transport, or mitochondrial fatty acid transport triggered expression of the MCU gatekeeper MICU1 but not the MCU core subunit. Knockdown of mitochondrial pyruvate carrier (MPC) isoforms or expression of the dominant negative mutant MPC1 R97W resulted in increased MICU1 protein abundance and inhibition of MCU-mediated mitochondrial matrix uptake of Ca 2+. We also found that genetic ablation of MPC1 in hepatocytes and mouse embryonic fibroblasts resulted in reduced resting matrix Ca 2+, likely because of increased MICU1 expression, but resulted in changes in mitochondrial morphology. TCA cycle substrate–dependent MICU1 expression was mediated by the transcription factor early growth response 1 (EGR1). Blocking mitochondrial pyruvate or fatty acid flux was linked to increased autophagy marker abundance. These studies reveal a mechanism that controls the MCU-mediated Ca 2+ flux machinery and that depends on TCA cycle substrate availability. This mechanism generates a metabolic homeostatic circuit that protects cells from bioenergetic crisis and mitochondrial Ca 2+ overload during periods of nutrient stress.

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          Most cited references50

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          A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans.

          Pyruvate constitutes a critical branch point in cellular carbon metabolism. We have identified two proteins, Mpc1 and Mpc2, as essential for mitochondrial pyruvate transport in yeast, Drosophila, and humans. Mpc1 and Mpc2 associate to form an ~150-kilodalton complex in the inner mitochondrial membrane. Yeast and Drosophila mutants lacking MPC1 display impaired pyruvate metabolism, with an accumulation of upstream metabolites and a depletion of tricarboxylic acid cycle intermediates. Loss of yeast Mpc1 results in defective mitochondrial pyruvate uptake, and silencing of MPC1 or MPC2 in mammalian cells impairs pyruvate oxidation. A point mutation in MPC1 provides resistance to a known inhibitor of the mitochondrial pyruvate carrier. Human genetic studies of three families with children suffering from lactic acidosis and hyperpyruvatemia revealed a causal locus that mapped to MPC1, changing single amino acids that are conserved throughout eukaryotes. These data demonstrate that Mpc1 and Mpc2 form an essential part of the mitochondrial pyruvate carrier.
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            MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca²⁺ uniporter.

            Mitochondrial Ca(2+) uptake via the uniporter is central to cell metabolism, signaling, and survival. Recent studies identified MCU as the uniporter's likely pore and MICU1, an EF-hand protein, as its critical regulator. How this complex decodes dynamic cytoplasmic [Ca(2+)] ([Ca(2+)]c) signals, to tune out small [Ca(2+)]c increases yet permit pulse transmission, remains unknown. We report that loss of MICU1 in mouse liver and cultured cells causes mitochondrial Ca(2+) accumulation during small [Ca(2+)]c elevations but an attenuated response to agonist-induced [Ca(2+)]c pulses. The latter reflects loss of positive cooperativity, likely via the EF-hands. MICU1 faces the intermembrane space and responds to [Ca(2+)]c changes. Prolonged MICU1 loss leads to an adaptive increase in matrix Ca(2+) binding, yet cells show impaired oxidative metabolism and sensitization to Ca(2+) overload. Collectively, the data indicate that MICU1 senses the [Ca(2+)]c to establish the uniporter's threshold and gain, thereby allowing mitochondria to properly decode different inputs. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Autophagy in metazoans: cell survival in the land of plenty.

              Cells require a constant supply of macromolecular precursors and oxidizable substrates to maintain viability. Unicellular eukaryotes lack the ability to regulate nutrient concentrations in their extracellular environment. So when environmental nutrients are depleted, these organisms catabolize existing cytoplasmic components to support ATP production to maintain survival, a process known as autophagy. By contrast, the environment of metazoans normally contains abundant extracellular nutrients, but a cell's ability to take up these nutrients is controlled by growth factor signal transduction. Despite evolving the ability to maintain a constant supply of extracellular nutrients, metazoans have retained a complete set of autophagy genes. The physiological relevance of autophagy in such species is just beginning to be explored.
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                Author and article information

                Journal
                Science Signaling
                Sci. Signal.
                American Association for the Advancement of Science (AAAS)
                1945-0877
                1937-9145
                April 21 2020
                April 21 2020
                April 21 2020
                April 21 2020
                : 13
                : 628
                : eaaz6206
                Affiliations
                [1 ]Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
                [2 ]Center for Translational Medicine, Lewis Katz School of Me.dicine at Temple University, Philadelphia, PA, 19140, USA.
                [3 ]Department of Medicine/Nephrology Division, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
                [4 ]Heart and Vascular Institute, Department of Medicine and Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, PA 17601, USA.
                [5 ]Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
                [6 ]Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA 19140, USA.
                [7 ]Department of Medicine/Diabetes Division, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
                [8 ]Pathology & Laboratory Medicine, Neurology, Neurosurgery, and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
                [9 ]Department of Periodontics, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
                Article
                10.1126/scisignal.aaz6206
                7667998
                32317369
                a3428697-1fa3-4154-bec5-2c66c81ec4de
                © 2020

                http://www.sciencemag.org/about/science-licenses-journal-article-reuse

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