PERK Signaling Promotes Mitochondrial Elongation By Remodeling Membrane Phosphatidic Acid

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are linked in the onset and pathogenesis of numerous diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria during ER stress. The PERK signaling arm of the unfolded protein response (UPR) has emerged as a prominent ER stress-responsive signaling pathway that regulates diverse aspects of mitochondrial biology. Here, we show that PERK activity promotes adaptive remodeling of mitochondrial membrane phosphatidic acid (PA) to induce protective mitochondrial elongation during acute ER stress. We find that PERK activity is required for ER stress-dependent increases in both cellular PA and YME1L-dependent degradation of the intramitochondrial PA transporter PRELID1. These two processes lead to the accumulation of PA on the outer mitochondrial membrane where it can induce mitochondrial elongation by inhibiting mitochondrial fission. Our results establish a new role for PERK in the adaptive remodeling of mitochondrial phospholipids and demonstrate that PERK-dependent PA regulation adapts organellar shape in response to ER stress.内质网（ER）应激与线粒体功能障碍在诸多疾病的发病与致病机制中密切相关。这一关联引发了学界对明确内质网应激期间调控线粒体机制的广泛关注。未折叠蛋白反应（UPR）的PERK信号分支作为一类关键的内质网应激响应信号通路，可调控线粒体生物学过程的多个方面。在此项研究中，我们证实PERK活性可促进线粒体膜磷脂酸（PA）的适应性重塑，从而在急性内质网应激期间诱导具有保护作用的线粒体伸长。我们发现，PERK活性对于内质网应激依赖的细胞内PA水平升高，以及线粒体内PA转运蛋白PRELID1的YME1L依赖性降解均不可或缺。这两个过程共同促使磷脂酸在线粒体外膜上积累，进而通过抑制线粒体分裂诱导线粒体伸长。本研究结果确立了PERK在线粒体磷脂适应性重塑中的全新功能，并证实PERK依赖性的PA调控可响应内质网应激，重塑细胞器形态。