Dhanabalan Karthik, Mzezewa Sibonginkosi, Huisamen Barbara, Lochner Amanda
Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Stellenbosch, PO Box 241, Cape Town, 8000, South Africa.
Cardiovasc Drugs Ther. 2020 Dec;34(6):799-811. doi: 10.1007/s10557-020-06997-9.
Oxidative stress causes mitochondrial dysfunction in myocardial ischaemia/reperfusion (I/R) as well as in obesity. Mitochondrial depolarization triggers mitophagy to degrade damaged mitochondria, a process important for quality control. The aims of this study were to evaluate (i) the effect of I/R on mitochondrial oxidative phosphorylation and its temporal relationship with mitophagy in hearts from obese rats and their age-matched controls, and (ii) the role of oxidative stress in these processes using melatonin, a free radical scavenger.
Male Wistar rats were divided into 4 groups: control (normal diet ± melatonin) and high-fat sucrose diet (HFSD ± melatonin). Rats received melatonin orally (10 mg/kg/day). After 16 weeks, hearts were removed and subjected to 40-min stabilization, and 25-min global ischaemia/10-min reperfusion for preparation of mitochondria. Mitochondrial oxidative phosphorylation was measured polarographically. Western blotting was used for evaluation of PINK1, Parkin, p62/SQSTM1 (p62) and TOM 70. Infarct size was measured using tetrazolium staining.
Ischaemia and reperfusion respectively reduced and increased mitochondrial QO2 (state 3) and the ox-phos rate in both control and HFSD mitochondria, showing no major changes between the groups, while melatonin pretreatment had little effect. p62 as indicator of mitophagic flux showed up- and downregulation of mitophagy by ischaemia and reperfusion respectively, with melatonin having no significant effect. Melatonin treatment caused a significant reduction in infarct size in hearts from both control and diet groups.
The results suggest that I/R (i) affects mitochondria from control and HFSD hearts similarly and (ii) melatonin-induced cardioprotection is not associated with reversal of mitochondrial dysfunction or changes in the PINK1/Parkin pathway.
氧化应激在心肌缺血/再灌注（I/R）以及肥胖过程中会导致线粒体功能障碍。线粒体去极化会触发线粒体自噬以降解受损的线粒体，这一过程对质量控制很重要。本研究的目的是评估：（i）I/R对肥胖大鼠及其年龄匹配的对照大鼠心脏中线粒体氧化磷酸化的影响及其与线粒体自噬的时间关系；（ii）使用褪黑素（一种自由基清除剂）来研究氧化应激在这些过程中的作用。
将雄性Wistar大鼠分为4组：对照组（正常饮食±褪黑素）和高脂蔗糖饮食组（HFSD±褪黑素）。大鼠口服褪黑素（10mg/kg/天）。16周后，取出心脏，进行40分钟的稳定处理，然后进行25分钟的全心缺血/10分钟再灌注以制备线粒体。用极谱法测量线粒体氧化磷酸化。采用蛋白质免疫印迹法评估PINK1、Parkin、p62/SQSTM1（p62）和TOM 70。用四氮唑染色法测量梗死面积。
缺血和再灌注分别降低和增加了对照组和HFSD组线粒体的QO2（状态3）和氧化磷酸化速率，两组之间无重大变化，而褪黑素预处理几乎没有影响。作为线粒体自噬通量指标的p62显示，缺血和再灌注分别上调和下调了线粒体自噬，褪黑素无显著影响。褪黑素治疗使对照组和饮食组心脏的梗死面积显著减小。
结果表明，I/R（i）对对照组和HFSD组心脏中的线粒体影响相似；（ii）褪黑素诱导的心脏保护作用与线粒体功能障碍的逆转或PINK1/Parkin途径的变化无关。
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