Lee Jason E, Westrate Laura M, Wu Haoxi, Page Cynthia, Voeltz Gia K
Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Boulder, Colorado 80309, USA.
Nature. 2016 Dec 1;540(7631):139-143. doi: 10.1038/nature20555. Epub 2016 Oct 31.
Mitochondria cannot be generated de novo; they must grow, replicate their genome, and divide in order to be inherited by each daughter cell during mitosis. Mitochondrial division is a structural challenge that requires the substantial remodelling of membrane morphology. Although division factors differ across organisms, the need for multiple constriction steps and a dynamin-related protein (Drp1, Dnm1 in yeast) has been conserved. In mammalian cells, mitochondrial division has been shown to proceed with at least two sequential constriction steps: the endoplasmic reticulum and actin must first collaborate to generate constrictions suitable for Drp1 assembly on the mitochondrial outer membrane; Drp1 then further constricts membranes until mitochondrial fission occurs. In vitro experiments, however, indicate that Drp1 does not have the dynamic range to complete membrane fission. In contrast to Drp1, the neuron-specific classical dynamin dynamin-1 (Dyn1) has been shown to assemble on narrower lipid profiles and facilitate spontaneous membrane fission upon GTP hydrolysis. Here we report that the ubiquitously expressed classical dynamin-2 (Dyn2) is a fundamental component of the mitochondrial division machinery. A combination of live-cell and electron microscopy in three different mammalian cell lines reveals that Dyn2 works in concert with Drp1 to orchestrate sequential constriction events that build up to division. Our work underscores the biophysical limitations of Drp1 and positions Dyn2, which has intrinsic membrane fission properties, at the final step of mitochondrial division.
线粒体无法从头生成；它们必须生长、复制其基因组并进行分裂，以便在有丝分裂期间被每个子细胞继承。线粒体分裂是一项结构挑战，需要对膜形态进行大量重塑。尽管不同生物体中的分裂因子有所不同，但多个收缩步骤以及一种与发动蛋白相关的蛋白质（酵母中的Drp1、Dnm1）的需求一直保留着。在哺乳动物细胞中，线粒体分裂已被证明至少通过两个连续的收缩步骤进行：内质网和肌动蛋白必须首先协同作用，在线粒体外膜上产生适合Drp1组装的收缩；然后Drp1进一步收缩膜，直到线粒体分裂发生。然而，体外实验表明，Drp1没有完成膜分裂的动态范围。与Drp1不同，神经元特异性经典发动蛋白发动蛋白-1（Dyn1）已被证明能在更窄的脂质轮廓上组装，并在GTP水解时促进自发膜分裂。在这里，我们报告普遍表达的经典发动蛋白-2（Dyn2）是线粒体分裂机制的一个基本组成部分。在三种不同的哺乳动物细胞系中进行的活细胞和电子显微镜观察相结合的结果表明，Dyn2与Drp1协同工作，协调一系列导致分裂的连续收缩事件。我们的工作强调了Drp1的生物物理局限性，并将具有内在膜分裂特性的Dyn2定位在线粒体分裂的最后一步。
