Small molecule inhibitors of mitochondrial division: tools that translate basic biological research into medicine.
Small molecule inhibitors of mitochondrial division: tools that translate basic biological research into medicine.
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DOI：
10.1016/j.chembiol.2010.05.016
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发表时间：
2010-06-25
影响因子：
--
通讯作者：
Nunnari J
中科院分区：
文献类型：
--
作者：
Lackner LL;Nunnari J
线粒体并不是离散的、静止的实体。相反，线粒体形成了一个不断移动、分裂和融合的网络。这个动态网络的结构部分地由分裂和融合事件的平衡来维持。定义适当平衡的分裂与融合事件的比率不是普遍的，而是随着发育阶段、细胞类型和生物环境而变化。这在高等真核生物的整个细胞周期中是明显的，其中线粒体在G1/S转换期间伸长并在有丝分裂开始时片段化，以及当线粒体响应于某些细胞刺激（例如细胞溶质钙水平的增加）而片段化时。线粒体的功能状态和分布明显受其稳态结构的影响。当分裂和融合的正常平衡被破坏的结果是不适当的刺激或抑制的过程中，出现的问题，在细胞水平上，损害健康的有机体作为一个整体。这是显而易见的，越来越多的疾病，其中异常线粒体动力学已被病因牵连。在这种情况下，线粒体分裂和融合机器是小分子效应物的有价值和有趣的靶标，因为这些过程的抑制或激活可能能够恢复适当的动态平衡和功能。线粒体分裂的小分子抑制剂mdivi-1已经被鉴定和表征。这种抑制剂为线粒体分裂机制提供了有价值的见解，并在广泛的疾病模型中显示出巨大的治疗前景。本文就线粒体分裂小分子效应物的研究进展、在基础生物学研究中的应用价值及其治疗潜力作一综述。
Mitochondria do not exist as discrete, static entities. Rather, mitochondria form a network that continuously moves, divides and fuses. The structure of this dynamic network is in part maintained by a balance of division and fusion events. The ratio of division to fusion events that defines a proper balance is not universal but varies with developmental stage, cell type and biological circumstances. This is evident throughout the cell cycle in higher eukaryotes, where mitochondria elongate during the G1/S transition and fragment at the onset of mitosis, and when mitochondria fragment in response to certain cellular stimuli, such as increases in cytosolic calcium levels. The functional state and distribution of mitochondria are clearly influenced by its steady-state structure. When the normal balance of division and fusion is disrupted as a consequence of the inappropriate stimulation or inhibition of either process, problems arise at the cellular level that compromise the well-being of the organism as a whole. This is evident by the ever-increasing number of diseases in which abnormal mitochondrial dynamics have been etiologically implicated. In this context, the mitochondrial division and fusion machines are valuable and interesting targets of small molecule effectors as inhibition or activation of these processes may be able to restore the proper dynamic balance and function. A small molecule inhibitor of mitochondrial division, mdivi-1, has already been identified and characterized. This inhibitor has provided valuable insight into the mechanism of mitochondrial division and has shown great therapeutic promise in a wide array of disease models. This review will focus on small molecule effectors of mitochondrial division, discussing their value in basic biological research as well as their therapeutic potential.
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