Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK.
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3B 2B4, Canada.
Science. 2020 Mar 20;367(6484):1366-1371. doi: 10.1126/science.aax6089.
Mitochondrial plasticity is a key regulator of cell fate decisions. Mitochondrial division involves Dynamin-related protein-1 (Drp1) oligomerization, which constricts membranes at endoplasmic reticulum (ER) contact sites. The mechanisms driving the final steps of mitochondrial division are still unclear. Here, we found that microdomains of phosphatidylinositol 4-phosphate [PI(4)P] on trans-Golgi network (TGN) vesicles were recruited to mitochondria-ER contact sites and could drive mitochondrial division downstream of Drp1. The loss of the small guanosine triphosphatase ADP-ribosylation factor 1 (Arf1) or its effector, phosphatidylinositol 4-kinase IIIβ [PI(4)KIIIβ], in different mammalian cell lines prevented PI(4)P generation and led to a hyperfused and branched mitochondrial network marked with extended mitochondrial constriction sites. Thus, recruitment of TGN-PI(4)P-containing vesicles at mitochondria-ER contact sites may trigger final events leading to mitochondrial scission.
线粒体的可塑性是细胞命运决定的关键调节因子。线粒体分裂涉及与 GTP 酶 dynamin 相关蛋白 1（Drp1）寡聚化，它在内质网（ER）接触部位收缩膜。驱动线粒体分裂的最后步骤的机制仍不清楚。在这里，我们发现磷酸肌醇 4-磷酸 [PI(4)P] 的微域被募集到线粒体 ER 接触部位，并能在 Drp1 下游驱动线粒体分裂。在不同的哺乳动物细胞系中，小 GTP 酶 ADP-核糖基化因子 1（Arf1）或其效应物，磷脂酰肌醇 4-激酶 IIIβ [PI(4)KIIIβ] 的缺失阻止了 PI(4)P 的产生，并导致超融合和分支的线粒体网络，其特征是线粒体收缩部位的延长。因此，TGN-PI(4)P 包含的囊泡在线粒体 ER 接触部位的募集可能触发导致线粒体分裂的最后事件。
