Regulating a uniter: control of mitofusin 2 expression.
Regulating a uniter: control of mitofusin 2 expression.
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调节单位：控制线粒体融合蛋白 2 的表达。
DOI：
10.1093/cvr/cvs101
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发表时间：
2012
影响因子：
10.8
通讯作者：
Chen,Le
中科院分区：
文献类型：
--
作者：
Knowlton,AnneA;Chen,Le
Sorianello et al. 1提供了关于线粒体融合蛋白（Mfn）2表达调控的重要新信息。线粒体分裂和融合最早在20世纪90年代在酵母中被描述，并被发现是维持健康线粒体所必需的过程。这项工作的主要发现包括线粒体不断分裂和融合（裂变和融合），裂变和融合对于维持线粒体健康至关重要（尽管确切原因仍有争议），以及线粒体作为相互连接的网络存在。[2]在酵母细胞中，分裂和融合的频率为每2分钟一次，但在哺乳动物细胞中，分裂和融合的速度要慢得多，需要数小时或更长时间。3，4最初有人怀疑高度组织和密集的心肌细胞中的线粒体是否能够进行裂变和融合，但越来越清楚的是，裂变和融合是所有细胞中的重要过程。5，6越来越明显的是，异常的裂变和聚变会导致心血管疾病。7. OPA 1在缺血性心肌病中降低，而Mfn 1/2在缺血性和非缺血性心力衰竭中均升高。8.单独缺失Mfn 2可导致轻度心脏肥大，功能变化极小。然而，Mfn 2的缺乏延迟了线粒体通透性转换，保护心肌细胞免受损伤并改善缺血/再灌注损伤后心脏的恢复。有趣的是，这些心脏的Bcl 2表达增加。相比之下，敲除心肌细胞中的Mfn 1和Mfn 2在胚胎中是致命的，而在成年小鼠心脏中诱导敲除这两种蛋白质导致线粒体片段化，线粒体呼吸抑制和扩张型心肌病，这是致命的。6线粒体分裂的抑制保护心脏免受缺血/再灌注损伤。10裂变和融合蛋白也在细胞凋亡中起作用。因此，这些蛋白质在细胞中具有线粒体分裂和融合以外的功能。Mfn 2以前也被认为是增生抑制基因，并且已经显示出在大鼠颈动脉中的培养物和球囊损伤后都能防止血管平滑肌细胞（VSMC）增殖。12 Mfn 2的过表达导致p21和p27表达增加和细胞周期停滞，抑制VSMC增殖而不增加凋亡。12类似地，在兔模型中，Mfn 2的过表达阻断LDL诱导的VSMC增殖并减少动脉粥样硬化形成。在糖尿病和肥胖症中，骨骼肌中的Mfn 2表达减少，并且这可以通过运动至少部分逆转。因此，有许多发现表明Mfn 2和血管疾病之间存在重要联系。此外，对Mfn 2的研究支持Mfn 2在代谢控制中的作用，这是Zorzano小组一直倡导的立场。16
Sorianello et al. 1 provide important new information on the regulation on mitofusin (Mfn) 2 expression. Mitochondrial fission and fusion were first described in yeast in the 1990s and found to be processes that are essential to maintain healthy mitochondria. Key findings from this work include that mitochondria continuously divide and fuse (fission and fusion), that fission and fusion are essential to maintain mitochondrial health (although the exact reason for this is a subject of debate), and that mitochondria exist as interconnected networks. 2 Fission and fusion occur as frequently as every 2 min in yeast, but are thought to occur much more slowly in mammalian cells, taking hours or longer. 3, 4 There initially had been scepticism that the mitochondria in the highly organized and densely packed cardiac myocyte would be able to undergo fission and fusion, but it is becoming clear that fission and fusion are important processes in all cells. 5, 6 It is increasingly evident that abnormal fission and fusion contribute to cardiovascular disease. 7 OPA1 has been found to be decreased in ischaemic cardiomyopathy, while Mfn1/2 were increased in both ischaemic and non-ischaemic heart failure. 8 Deletion of Mfn 2 alone resulted in mild cardiac hypertrophy with very minor changes in function. 9 However, the absence of Mfn2 delayed the mitochondrial permeability transition, protecting cardiac myocytes from injury and improving the recovery of the heart after ischaemia/reperfusion injury. 9 Interestingly, these hearts had increased expression of Bcl2. In contrast, knockout of Mfn1 and Mfn2 in cardiac myocytes was lethal in embryos, while induction of knockdown of these two proteins in the adult mouse heart resulted in mitochondrial fragmentation, depressed mitochondrial respiration, and a dilated cardiomyopathy, which was fatal. 6 Inhibition of mitochondrial fission protected the heart against ischaemia/reperfusion injury. 10 Fission and fusion proteins also have a role in apoptosis. 11 Thus, these proteins have functions in the cell beyond mitochondrial fission and fusion.Mfn2 was previously known also as hyperplasia suppressor gene and has been shown to prevent vascular smooth muscle cell (VSMC) proliferation both in culture and following balloon injury in the rat carotid. 12 Overexpression of Mfn2 leads to increased expression of p21 and p27 and cell cycle arrest, inhibiting VSMC proliferation without an increase in apoptosis. 12 Similarly, overexpression of Mfn2 blocked LDL-induced VSMC proliferation and decreased atherogenesis in a rabbit model. 13 Mfn2 expression is decreased in the skeletal muscle in both diabetes and obesity, and this can be at least partially reversed by exercise. 14, 15 Thus, there are a number of findings that suggest an important link between Mfn2 and vascular disease. In addition, work on Mfn2 supports a role for Mfn2 in metabolic control, a position that has been championed by the Zorzano group. 16