title: GLP-1 promotes mitochondrial metabolism in vascular smooth muscle cells by enhancing endoplasmic reticulum-mitochondria coupling.
abstract: Incretin GLP-1 has important metabolic effects on several tissues, mainly through the regulation of glucose uptake and usage. One mechanism for increasing cell metabolism is modulating endoplasmic reticulum (ER)-mitochondria communication, as it allows for a more efficient transfer of Ca(2+) into the mitochondria, thereby increasing activity. Control of glucose metabolism is essential for proper vascular smooth muscle cell (VSMC) function. GLP-1 has been shown to produce varied metabolic actions, but whether it regulates glucose metabolism in VSMC remains unknown. In this report, we show that GLP-1 increases mitochondrial activity in the aortic cell line A7r5 by increasing ER-mitochondria coupling. GLP-1 increases intracellular glucose and diminishes glucose uptake without altering glycogen content. ATP, mitochondrial potential and oxygen consumption increase at 3h of GLP-1 treatment, paralleled by increased Ca(2+) transfer from the ER to the mitochondria. Furthermore, GLP-1 increases levels of Mitofusin-2 (Mfn2), an ER-mitochondria tethering protein, via a PKA-dependent mechanism. Accordingly, PKA inhibition and Mfn2 down-regulation prevented mitochondrial Ca(2+) increases in GLP-1 treated cells. Inhibiting both Ca(2+) release from the ER and Ca(2+) entry into mitochondria as well as diminishing Mfn2 levels blunted the increase in mitochondrial activity in response to GLP-1. Altogether, these results strongly suggest that GLP-1 increases ER-mitochondria communication in VSMC, resulting in higher mitochondrial activity.
authors.affiliation: Advanced Center for Chronic Diseases, Centro Estudios Moleculares de la Célula, Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Morales
authors.affiliation: Advanced Center for Chronic Diseases, Centro Estudios Moleculares de la Célula, Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Gloria
authors.initials: G
authors.lastname: Torres
authors.affiliation: Advanced Center for Chronic Diseases, Centro Estudios Moleculares de la Célula, Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Cristian
authors.initials: C
authors.lastname: Sotomayor-Flores
authors.affiliation: Advanced Center for Chronic Diseases, Centro Estudios Moleculares de la Célula, Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Daniel
authors.initials: D
authors.lastname: Peña-Oyarzún
authors.affiliation: Advanced Center for Chronic Diseases, Centro Estudios Moleculares de la Célula, Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Pablo
authors.initials: P
authors.lastname: Rivera-Mejías
authors.affiliation: Advanced Center for Chronic Diseases, Centro Estudios Moleculares de la Célula, Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Felipe
authors.initials: F
authors.lastname: Paredes
authors.affiliation: Advanced Center for Chronic Diseases, Centro Estudios Moleculares de la Célula, Departamento Bioquímica y Biología Molecular, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile. Electronic address: mchiong@uchile.cl.
authors.forename: Mario
authors.initials: M
authors.lastname: Chiong
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D020558:GTP Phosphohydrolases; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D051381:Rats; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism
chemical_list: C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D000255:Adenosine Triphosphate; D006003:Glycogen; D017868:Cyclic AMP-Dependent Protein Kinases; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat; D005947:Glucose; D002118:Calcium
keywords: ER–mitochondria coupling; GLP-1; Mitochondrial metabolism; Mitofusin-2; PKA; VSMC