Impaired phosphatidylethanolamine metabolism activates a reversible stress response that detects and resolves mutant mitochondrial precursors

Phosphatidylethanolamine made in mitochondria has long been recognized as an important precursor for phosphatidylcholine production that occurs in the endoplasmic reticulum (ER). Recently, the strict mitochondrial localization of the enzyme that makes PE in the mitochondrion, phosphatidylserine decarboxylase 1 (Psd1), was questioned. Since a dual localization of Psd1 to the ER would have far-reaching implications, we initiated our study to independently re-assess the subcellular distribution of Psd1. Our results support the unavoidable conclusion that the vast majority, if not all, of functional Psd1 resides in the mitochondrion. Through our efforts, we discovered that mutant forms of Psd1 that impair a self-processing step needed for it to become functional are dually localized to the ER when expressed in a PE-limiting environment. We conclude that severely impaired cellular PE metabolism provokes an ER-assisted adaptive response that is capable of identifying and resolving nonfunctional mitochondrial precursors.长期以来，线粒体内合成的磷脂酰乙醇胺（phosphatidylethanolamine, PE）一直被视作在内质网（endoplasmic reticulum, ER）中合成磷脂酰胆碱的重要前体。近期，学界对线粒体内合成PE的酶——磷脂酰丝氨酸脱羧酶1（phosphatidylserine decarboxylase 1, Psd1）的严格线粒体定位这一论断提出了质疑。鉴于Psd1若同时定位于内质网将产生深远影响，我们启动本研究以独立重新评估Psd1的亚细胞分布。我们的研究结果支持了一项无可辩驳的结论：即便并非全部，绝大多数具有功能活性的Psd1均定位于线粒体中。本研究还发现，当在磷脂酰乙醇胺限制环境中表达时，损害Psd1实现功能所需的自我加工步骤的突变型Psd1会同时定位于内质网。综上，我们认为严重受损的细胞磷脂酰乙醇胺代谢会触发一种依赖内质网的适应性应答，该应答能够识别并清除无功能的线粒体前体蛋白。