Schiffer 2016 Am J Physiol Cell Physiol
|Schiffer TA, Peleli M, Sundqvist ML, Ekblom B, Lundberg JO, Weitzberg E, Larsen FJ (2016) Control of human energy expenditure by cytochrome c oxidase subunit IV-2. Am J Physiol Cell Physiol 311:C452-61.|
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.
Copyright © 2016 the American Physiological Society. • Keywords: High-resolution respirometry, Mitochondria, Resting metabolic rate • Bioblast editor: Kandolf G • O2k-Network Lab: SE Uppsala Liss P, SE Stockholm Sahlin K, SE Stockholm Weitzberg E, SE Stockholm Larsen FJ
Labels: MiParea: Respiration, Genetic knockout;overexpression
Stress:Oxidative stress;RONS, Hypoxia Organism: Human Tissue;cell: Skeletal muscle, HEK Preparation: Intact cells, Permeabilized cells, Isolated mitochondria Enzyme: Complex IV;cytochrome c oxidase Regulation: Oxygen kinetics Coupling state: LEAK, ROUTINE, OXPHOS, ET Pathway: N, NS HRR: Oxygraph-2k, TIP2k, O2k-Fluorometer