Mitochondrial OPA1, apoptosis, and heart failure
Mitochondrial OPA1, apoptosis, and heart failure
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DOI：
10.1093/cvr/cvp181
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发表时间：
2009-10-01
影响因子：
10.8
通讯作者：
Knowlton, Anne A.
中科院分区：
文献类型：
--
作者：
Chen, Le;Gong, Qizhi;Knowlton, Anne A.
线粒体融合和分裂是维持正常线粒体功能的重要过程。我们假设融合蛋白在心力衰竭（HF）中会减少，因为已报道HF中的线粒体较小且功能失调。OPA 1对于维持正常嵴结构和功能、保护内膜结构和保护细胞免于凋亡是重要的。共聚焦显微镜和电子显微镜研究表明，衰竭心脏中的线粒体很小且碎片化，与融合减少一致。OPA 1 mRNA水平在衰竭心脏和正常心脏之间没有差异，表明转录后控制。心肌细胞系H9 c2细胞中的模拟缺血降低了OPA蛋白水平。用shRNA减少OPA 1表达导致线粒体凋亡和碎片增加。OPA 1的过表达增加线粒体微管，但不能防止模拟缺血诱导的细胞凋亡。线粒体细胞色素c的释放随着OPA 1的减少和OPA 1的过表达而增加。据我们所知，这是第一份关于心血管疾病中线粒体融合/分裂蛋白变化的报告。这些变化对线粒体功能和细胞凋亡有影响，导致细胞损失，这是衰竭心脏向下进展的一部分。
Mitochondrial fusion and fission are essential processes for preservation of normal mitochondrial function. We hypothesized that fusion proteins would be decreased in heart failure (HF), as the mitochondria in HF have been reported to be small and dysfunctional.Expression of optic atrophy 1 (OPA1), a mitochondrial fusion protein, was decreased in both human and rat HF, as observed by western blotting. OPA1 is important for maintaining normal cristae structure and function, for preserving the inner membrane structure and for protecting cells from apoptosis. Confocal and electron microscopy studies demonstrated that the mitochondria in the failing hearts were small and fragmented, consistent with decreased fusion. OPA1 mRNA levels did not differ between failing and normal hearts, suggesting post-transcriptional control. Simulated ischaemia in the cardiac myogenic cell line H9c2 cells reduced OPA protein levels. Reduction of OPA1 expression with shRNA resulted in increased apoptosis and fragmentation of the mitochondria. Overexpression of OPA1 increased mitochondrial tubularity, but did not protect against simulated ischaemia-induced apoptosis. Cytochrome c release from the mitochondria was increased both with reduction in OPA1 and with overexpression of OPA1.This is the first report, to our knowledge, of changes in mitochondrial fusion/fission proteins in cardiovascular disease. These changes have implications for mitochondrial function and apoptosis, contributing to the cell loss which is part of the downward progression of the failing heart.