Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression
Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression
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DOI：
10.1016/s0735-1097(02)02600-1
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发表时间：
2002-12-18
影响因子：
24
通讯作者：
Holtz, J
中科院分区：
文献类型：
--
作者：
Scheubel, RJ;Tostlebe, M;Holtz, J
目的 在衰竭的人类心肌中评估具有或不具有线粒体编码亚基的线粒体呼吸链复合物的活性以及线粒体基因表达的参数。背景线粒体基因组（mtDNA）的突变和缺失在衰老的心肌中零星地积累。在实验性心力衰竭中，它们被认为是导致线粒体基因表达和线粒体功能紊乱的普遍问题。 方法 在 43 颗摘除的衰竭心脏和 10 颗供体心脏的左心室标本中，检测呼吸链复合物的酶活性、线粒体和核编码的线粒体成分的信使核糖核酸 (mRNA) 表达（逆转录酶聚合酶链反应、Northern 印迹）、未删除的野生型 mtDNA（Southern 印迹）和核编码的 mtDNA。对线粒体转录因子 A (mtTFA)（蛋白质印迹）进行定量。结果 线粒体呼吸链复合物 1（包含七个线粒体编码亚基）的柠檬酸合酶标准化活性在终末衰竭心肌中降低了 28%，而仅由核编码的复合物 11 的活性没有变化。然而，与供体心脏相比，完整线粒体DNA的量、整个呼吸链的所有线粒体编码亚基的mRNA、mtTFA的量以及复合物III和复合物IV（也含有线粒体编码亚基）的酶活性均正常，排除线粒体基因表达的普遍紊乱。移植前药物治疗的回顾性分析确定β受体阻滞剂是对抗这种干扰的一种假定保护措施。结论在接受药物治疗的患者的终末衰竭人类心肌中，复合物I抑制不是由mtDNA损伤和线粒体基因表达紊乱引起的。如果能够实现有效的卸载，那么线粒体DNA损伤的缺失应该有利于超负荷心肌的恢复。 (C) 2002 年由美国心脏病学会基金会资助。
OBJECTIVES Activity of mitochondrial respiratory chain complexes with and without mitochondrially encoded subunits was assessed in failing human myocardium together with parameters of mitochondrial gene expression.BACKGROUND Mutations and deletions in mitochondrial genome (mtDNA) sporadically accumulate in the aging myocardium. In experimental heart failure, they are discussed to be a generalized problem resulting in disturbances of mitochondrial gene expression and mitochondrial function.METHODS In left ventricular specimens from 43 explanted failing hearts and 10 donor hearts, enzyme activities of respiratory chain complexes, messenger ribonucleic acid (mRNA) expression of mitochondrially and nuclear encoded mitochondrial components (reverse transcriptase-polymerase chain reaction, Northern blot), undeleted wildtype mtDNA (Southern blot), and nuclear encoded mitochondrial transcription factor A (mtTFA) (Western blot) were quantified.RESULTS Citrate synthase normalized activity of mitochondrial respiratory chain complex 1, which contains seven mitochondrially encoded subunits, was decreased by 28% in terminally failing myocardium, whereas the activity of the exclusively nuclear encoded complex 11 was unchanged. However, the amount of intact mtDNA, the mRNA of all mitochondrially encoded subunits of the entire respiratory chain, the amount of mtTFA, and the enzymatic activity of complex III and complex IV, which also contain mitochondrially encoded subunits, were normal compared with donor hearts, excluding generalized disturbance of mitochondrial gene expression. Retrospective analysis of drug therapy before transplantation identified beta-blockers as one putative protection against this disturbance.CONCLUSIONS In terminally failing human myocardium of patients receiving drug therapy, complex I depression is not caused by mtDNA damage and disturbed mitochondrial gene expression. The absence of mtDNA damage should facilitate recovery of the overloaded myocardium, if effective unloading could be achieved. (C) 2002 by the American College of Cardiology Foundation.