Department of Biology, Illinois Institute of Technology, Chicago, IL, United States of America.
PLoS One. 2020 Nov 19;15(11):e0242700. doi: 10.1371/journal.pone.0242700. eCollection 2020.
Mitochondrial fusion and fission are dynamic processes regulated by the cellular microenvironment. Under nutrient starvation conditions, mitochondrial fusion is strengthened for energy conservation. We have previously shown that newborns of Ubl4A-deficient mice were more sensitive to starvation stress with a higher rate of mortality than their wild-type littermates. Ubl4A binds with the actin-related protein Arp2/3 complex to synergize the actin branching process. Here, we showed that deficiency in Ubl4A resulted in mitochondrial fragmentation and apoptosis. A defect in the fusion process was the main cause of the mitochondrial fragmentation and resulted from a shortage of primed Arp2/3 complex pool around the mitochondria in the Ubl4A-deficient cells compared to the wild-type cells. As a result, the mitochondrial fusion process was not undertaken quickly enough to sustain starvation stress-induced cell death. Consequently, fragmented mitochondria lost their membrane integrity and ROS was accumulated to trigger caspase 9-dependent apoptosis before autophagic rescue. Furthermore, the wild-type Ubl4A, but not the Arp2/3-binding deficient mutant, could rescue the starvation-induced mitochondrial fragmentation phenotype. These results suggest that Ubl4A promotes the mitochondrial fusion process via Arp2/3 complex during the initial response to nutrient deprivation for cell survival.
线粒体融合和裂变是受细胞微环境调节的动态过程。在营养饥饿条件下，为了节约能量，线粒体融合会增强。我们之前曾表明，Ubl4A 缺陷型小鼠的新生仔鼠对饥饿应激更为敏感，死亡率高于其野生型同窝仔鼠。Ubl4A 与肌动蛋白相关蛋白 Arp2/3 复合物结合，协同肌动蛋白分支过程。在这里，我们发现 Ubl4A 缺乏会导致线粒体碎片化和细胞凋亡。融合过程的缺陷是线粒体碎片化的主要原因，与野生型细胞相比，Ubl4A 缺陷型细胞中线粒体周围的 Arp2/3 复合物储备不足，导致融合过程无法迅速进行，无法维持饥饿应激诱导的细胞死亡。因此，碎片化的线粒体失去了膜的完整性，ROS 积累触发 caspase 9 依赖性凋亡，然后进行自噬拯救。此外，野生型 Ubl4A，但不是 Arp2/3 结合缺陷突变体，能够挽救饥饿诱导的线粒体碎片化表型。这些结果表明，Ubl4A 通过 Arp2/3 复合物在细胞对营养缺乏的初始反应中促进线粒体融合过程，以维持细胞存活。
