National Institute of Biological Sciences, Beijing, China.
Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
PLoS Genet. 2020 Oct 16;16(10):e1009070. doi: 10.1371/journal.pgen.1009070. eCollection 2020 Oct.
The major glycerophospholipid phosphatidylethanolamine (PE) in the nervous system is essential for neural development and function. There are two major PE synthesis pathways, the CDP-ethanolamine pathway in the endoplasmic reticulum (ER) and the phosphatidylserine decarboxylase (PSD) pathway in mitochondria. However, the role played by mitochondrial PE synthesis in maintaining cellular PE homeostasis is unknown. Here, we show that Drosophila pect (phosphoethanolamine cytidylyltransferase) mutants lacking the CDP-ethanolamine pathway, exhibited alterations in phospholipid composition, defective phototransduction, and retinal degeneration. Induction of the PSD pathway fully restored levels and composition of cellular PE, thus rescued the retinal degeneration and defective visual responses in pect mutants. Disrupting lipid exchange between mitochondria and ER blocked the ability of PSD to rescue pect mutant phenotypes. These findings provide direct evidence that the synthesis of PE in mitochondria contributes to cellular PE homeostasis, and suggest the induction of mitochondrial PE synthesis as a promising therapeutic approach for disorders associated with PE deficiency.
神经系统中的主要甘油磷脂磷脂酰乙醇胺 (PE) 对神经发育和功能至关重要。有两种主要的 PE 合成途径，内质网 (ER) 中的 CDP-乙醇胺途径和线粒体中的磷脂酰丝氨酸脱羧酶 (PSD) 途径。然而，线粒体 PE 合成在维持细胞 PE 动态平衡中的作用尚不清楚。在这里，我们发现缺乏 CDP-乙醇胺途径的果蝇 pect（磷酸乙醇胺胞苷转移酶）突变体表现出磷脂组成改变、光转导缺陷和视网膜变性。诱导 PSD 途径可完全恢复细胞 PE 的水平和组成，从而挽救 pect 突变体的视网膜变性和视觉反应缺陷。阻断线粒体和 ER 之间的脂质交换会阻止 PSD 拯救 pect 突变体表型的能力。这些发现为线粒体中 PE 的合成有助于细胞 PE 动态平衡提供了直接证据，并表明诱导线粒体 PE 合成作为治疗与 PE 缺乏相关疾病的有前途的方法。
