Chang 2019 Br J Anaesth
|Chang L, Daly C, Miller DM, Allen PD, Boyle JP, Hopkins PM, Shaw MA (2019) Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals. Br J Anaesth 122:613-21.|
Abstract: Individuals genetically susceptible to malignant hyperthermia (MH) exhibit hypermetabolic reactions when exposed to volatile anaesthetics. Mitochondrial dysfunction has previously been associated with the MH-susceptible (MHS) phenotype in animal models, but evidence of this in human MH is limited.
We used high resolution respirometry to compare oxygen consumption rates (oxygen flux) between permeabilised human MHS and MH-negative (MHN) skeletal muscle fibres with or without prior exposure to halothane. A substrate-uncoupler-inhibitor titration protocol was used to measure the following components of the electron transport chain under conditions of oxidative phosphorylation (OXPHOS) or after uncoupling the electron transport system (ETS): complex I (CI), complex II (CII), CI+CII and, as a measure of mitochondrial mass, complex IV (CIV).
Baseline comparisons without halothane exposure showed significantly increased mitochondrial mass (CIV, P=0.021) but lower flux control ratios in CI+CII(OXPHOS) and CII(ETS) of MHS mitochondria compared with MHN (P=0.033 and 0.005, respectively) showing that human MHS mitochondria have a functional deficiency. Exposure to halothane triggered a hypermetabolic response in MHS mitochondria, significantly increasing mass-specific oxygen flux in CI(OXPHOS), CI+CII(OXPHOS), CI+CII(ETS), and CII(ETS) (P=0.001-0.012), while the rates in MHN samples were unaltered by halothane exposure.
We present evidence of mitochondrial dysfunction in human MHS skeletal muscle both at baseline and after halothane exposure.
Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
• Keywords: Electron transport chain, Malignant hyperthermia, Mitochondria, Oxidative phosphorylation, Skeletal muscle, Volatile anaesthetic • Bioblast editor: Plangger M • O2k-Network Lab: UK Leeds Peers C
Labels: MiParea: Pharmacology;toxicology
Stress:Temperature Organism: Human Tissue;cell: Skeletal muscle
Enzyme: Complex IV;cytochrome c oxidase Regulation: Flux control Coupling state: LEAK, OXPHOS, ET Pathway: N, S, CIV, NS, ROX