title: Calcineurin Links Mitochondrial Elongation with Energy Metabolism.
abstract: Canonical protein phosphatase 3/calcineurin signaling is central to numerous physiological processes. Here we provide evidence that calcineurin plays a pivotal role in controlling systemic energy and body weight homeostasis. Knockdown of calcineurin in Drosophila melanogaster led to a decrease in body weight and energy stores, and increased energy expenditure. In mice, global deficiency of catalytic subunit Ppp3cb, and tissue-specific ablation of regulatory subunit Ppp3r1 from skeletal muscle, but not adipose tissue or liver, led to protection from high-fat-diet-induced obesity and comorbid sequelæ. Ser637 hyperphosphorylation of dynamin-related protein 1 (Drp1) in skeletal muscle of calcineurin-deficient mice was associated with mitochondrial elongation into power-cable-shaped filaments and increased mitochondrial respiration, but also with attenuated exercise performance. Our data suggest that calcineurin acts as highly conserved pivot for the adaptive metabolic responses to environmental changes such as high-fat, high-sugar diets or exercise.
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Dhiraj G
authors.initials: DG
authors.lastname: Kabra
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Schriever
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Pfuhlmann
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Verónica Casquero
authors.initials: VC
authors.lastname: García
authors.affiliation: LIKES Research Center for Sport and Health Sciences, 40720 Jyväskylä, Finland.
authors.forename: Maarit
authors.initials: M
authors.lastname: Lehti
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH 45237, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Weber
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Kutschke
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz-Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.affiliation: Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Elrod
authors.affiliation: Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Hevener
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Feuchtinger
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz-Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.affiliation: Department of Biological Sciences, University of Cincinnati, Cincinnati, OH 45221, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Rollmann
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH 45237, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Jastroch
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: De Luca
authors.affiliation: Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany. Electronic address: matthias.tschoep@helmholtz-muenchen.de.
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
mesh_terms: D000818:Animals; D001835:Body Weight; D019703:Calcineurin / Q000235:genetics* / Q000378:metabolism; D002135:Calcium-Binding Proteins; D059305:Diet, High-Fat; D034281:Dynamins / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; C511512:DSCR1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D019703:Calcineurin; C557393:protein phosphatase 3, catalytic subunit, beta isoform, mouse; C486391:Dnm1l protein, mouse; D034281:Dynamins