title: ROS-triggered phosphorylation of complex II by Fgr kinase regulates cellular adaptation to fuel use.
abstract: Electron flux in the mitochondrial electron transport chain is determined by the superassembly of mitochondrial respiratory complexes. Different superassemblies are dedicated to receive electrons derived from NADH or FADH2, allowing cells to adapt to the particular NADH/FADH2 ratio generated from available fuel sources. When several fuels are available, cells adapt to the fuel best suited to their type or functional status (e.g., quiescent versus proliferative). We show that an appropriate proportion of superassemblies can be achieved by increasing CII activity through phosphorylation of the complex II catalytic subunit FpSDH. This phosphorylation is mediated by the tyrosine-kinase Fgr, which is activated by hydrogen peroxide. Ablation of Fgr or mutation of the FpSDH target tyrosine abolishes the capacity of mitochondria to adjust metabolism upon nutrient restriction, hypoxia/reoxygenation, and T cell activation, demonstrating the physiological relevance of this adaptive response.
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Acín-Pérez
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Carrascoso
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Baixauli
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Roche-Molina
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Latorre-Pellicer
authors.affiliation: Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain.
authors.forename: Patricio
authors.initials: P
authors.lastname: Fernández-Silva
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Mittelbrunn
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sanchez-Madrid
authors.affiliation: Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain.
authors.forename: Acisclo
authors.initials: A
authors.lastname: Pérez-Martos
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.affiliation: Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain; Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain. Electronic address: jaenriquez@cnic.es.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Enríquez
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D004579:Electron Transport / Q000502:physiology; D042963:Electron Transport Complex II / Q000378:metabolism*; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D013217:Starvation / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C000598559:FpSDH protein, mouse; D011518:Proto-Oncogene Proteins; D009243:NAD; D005182:Flavin-Adenine Dinucleotide; D006861:Hydrogen Peroxide; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases