Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals
Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals
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DOI：
10.1016/j.bja.2019.02.010
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发表时间：
2019-05-01
影响因子：
9.8
通讯作者：
Shaw, Marie-Anne
中科院分区：
文献类型：
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作者：
Chang, Leon;Daly, Catherine;Shaw, Marie-Anne
背景：当暴露于挥发性麻醉剂时，遗传上易患恶性高热（MH）的个体表现出高代谢反应。线粒体功能障碍以前已与MH-易感（MHS）的动物模型中的表型，但在人类MH的证据是limited.Methods：我们使用高分辨率呼吸测定法比较透化人类MHS和MH-阴性（MHN）骨骼肌纤维之间的耗氧率（氧通量）有或没有事先暴露于氟烷。底物-解偶联剂-抑制剂滴定方案用于在氧化磷酸化（OXPHOS）条件下或在解偶联电子传递系统（ETS）后测量电子传递链的以下组分：复合物I（Cl）、复合物II（CII）、Cl +CII和作为线粒体质量的量度的复合物IV（CIV）。无氟烷暴露的基线比较显示线粒体质量显著增加（CIV，P=0.021），但与MHN相比，MHS线粒体的CI+CII（OXPHOS）和CII（ETS）的流量控制率较低（分别为P=0.033和0.005），表明人MHS线粒体具有功能缺陷。暴露于氟烷引发MHS线粒体的高代谢反应，显着增加CI（OXPHOS），CI+CII（OXPHOS），CI + CII（ETS），和CII（ETS）（P=0.001-0.012）的质量比氧流量，而在MHN样品的速率未改变氟烷exposure.Conclusions：我们目前的证据表明，在人类MHS骨骼肌线粒体功能障碍，在基线和氟烷暴露后。
Background: 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.Methods: 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).Results: 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.Conclusions: We present evidence of mitochondrial dysfunction in human MHS skeletal muscle both at baseline and after halothane exposure.