title: Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca2+Signals Is Controlled by the Stoichiometry of MICU1/2 and MCU.
abstract: Mitochondrial Ca2+uptake through the Ca2+uniporter supports cell functions, including oxidative metabolism, while meeting tissue-specific calcium signaling patterns and energy needs. The molecular mechanisms underlying tissue-specific control of the uniporter are unknown. Here, we investigated a possible role for tissue-specific stoichiometry between the Ca2+-sensing regulators (MICUs) and pore unit (MCU) of the uniporter. Low MICU1:MCU protein ratio lowered the [Ca2+] threshold for Ca2+uptake and activation of oxidative metabolism but decreased the cooperativity of uniporter activation in heart and skeletal muscle compared to liver. In MICU1-overexpressing cells, MICU1 was pulled down by MCU proportionally to MICU1 overexpression, suggesting that MICU1:MCU protein ratio directly reflected their association. Overexpressing MICU1 in the heart increased MICU1:MCU ratio, leading to liver-like mitochondrial Ca2+uptake phenotype and cardiac contractile dysfunction. Thus, the proportion of MICU1-free and MICU1-associated MCU controls these tissue-specific uniporter phenotypes and downstream Ca2+tuning of oxidative metabolism.
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Paillard
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: György
authors.initials: G
authors.lastname: Csordás
authors.affiliation: Department of Physiology, Semmelweis University, Budapest 1085, Hungary.
authors.forename: Gergö
authors.initials: G
authors.lastname: Szanda
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Tünde
authors.initials: T
authors.lastname: Golenár
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Debattisti
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Bartok
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Nadan
authors.initials: N
authors.lastname: Wang
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Moffat
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Seifert
authors.affiliation: Department of Physiology, Semmelweis University, Budapest 1085, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Spät
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: gyorgy.hajnoczky@jefferson.edu.
authors.forename: György
authors.initials: G
authors.lastname: Hajnóczky
mesh_terms: D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity; D010084:Oxidation-Reduction
chemical_list: D015220:Calcium Channels; D002135:Calcium-Binding Proteins; C000610715:MICU1 protein, mouse; C000624978:Micu2 protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; C034703:mitochondrial calcium uniporter
keywords: calcium oscillations; calcium uniporter; signal decoding