title: Control of human energy expenditure by cytochrome c oxidase subunit IV-2.
abstract: Resting metabolic rate (RMR) in humans shows pronounced individual variations, but the underlying molecular mechanism remains elusive. Cytochrome c oxidase (COX) plays a key role in control of metabolic rate, and recent studies of the subunit 4 isoform 2 (COX IV-2) indicate involvement in the cellular response to hypoxia and oxidative stress. We evaluated whether the COX subunit IV isoform composition may explain the pronounced individual variations in resting metabolic rate (RMR). RMR was determined in healthy humans by indirect calorimetry and correlated to levels of COX IV-2 and COX IV-1 in vastus lateralis. Overexpression and knock down of the COX IV isoforms were performed in primary myotubes followed by evaluation of the cell respiration and production of reactive oxygen species. Here we show that COX IV-2 protein is constitutively expressed in human skeletal muscle and strongly correlated to RMR. Primary human myotubes overexpressing COX IV-2 displayed markedly (>60%) lower respiration, reduced (>50%) cellular H2O2 production, higher resistance toward both oxidative stress, and severe hypoxia compared with control cells. These results suggest an important role of isoform COX IV-2 in the control of energy expenditure, hypoxic tolerance, and mitochondrial ROS homeostasis in humans.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Schiffer
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Maria
authors.initials: M
authors.lastname: Peleli
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Michaela L
authors.initials: ML
authors.lastname: Sundqvist
authors.affiliation: Åstrand Laboratory of Work Physiology, Swedish School of Sport and Health Sciences, Stockholm, Sweden; and.
authors.forename: Björn
authors.initials: B
authors.lastname: Ekblom
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Jon O
authors.initials: JO
authors.lastname: Lundberg
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Anesthesia & Intensive Care, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Eddie
authors.initials: E
authors.lastname: Weitzberg
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Åstrand Laboratory of Work Physiology, Swedish School of Sport and Health Sciences, Stockholm, Sweden; and filip.larsen@gih.se.
authors.forename: Filip J
authors.initials: FJ
authors.lastname: Larsen
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D003576:Electron Transport Complex IV / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D003576:Electron Transport Complex IV
keywords: high-resolution respirometry; mitochondria; resting metabolic rate