Lackner Laura L, Nunnari Jodi
Department of Molecular and Cellular Biology, University of California, Davis, CA 95616, USA.
Chem Biol. 2010 Jun 25;17(6):578-83. doi: 10.1016/j.chembiol.2010.05.016.
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 (Hoppins et al., 2007). 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 (Breckenridge et al., 2003; Cereghetti et al., 2008; Han et al., 2008; Mitra et al., 2009; Taguchi et al., 2007). 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 compromises 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 (Cassidy-Stone et al., 2008). 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.
线粒体并非以离散的静态实体形式存在；相反，线粒体形成一个不断移动、分裂和融合的网络。这种动态网络的结构部分是由分裂和融合事件的平衡维持的（霍平斯等人，2007年）。定义适当平衡的分裂与融合事件的比例并非普遍适用，而是随发育阶段、细胞类型和生物学环境而变化。这在高等真核生物的整个细胞周期中都很明显，线粒体在G1/S期转换时伸长，在有丝分裂开始时碎片化，以及当线粒体因某些细胞刺激（如细胞质钙水平升高）而碎片化时（布雷肯里奇等人，2003年；切雷盖蒂等人，2008年；韩等人，2008年；米特拉等人，2009年；田口等人，2007年）。线粒体的功能状态和分布显然受到其稳态结构的影响。当由于对任何一个过程的不适当刺激或抑制而破坏了正常的分裂与融合平衡时，细胞水平就会出现问题，从而损害整个生物体的健康。这在越来越多的疾病中很明显，其中线粒体动力学异常在病因学上与之相关。在这种情况下，线粒体分裂和融合机制是小分子效应物有价值且有趣的靶点，因为抑制或激活这些过程可能能够恢复适当的动态平衡和功能。一种线粒体分裂的小分子抑制剂mdivi-1已经被鉴定和表征（卡西迪-斯通等人，2008年）。这种抑制剂为线粒体分裂机制提供了有价值的见解，并在一系列疾病模型中显示出巨大的治疗前景。本综述将聚焦于线粒体分裂的小分子效应物，讨论它们在基础生物学研究中的价值及其治疗潜力。
