Choline restores respiration in Psd1-deficient yeast by replenishing mitochondrial phosphatidylethanolamine.
Choline restores respiration in Psd1-deficient yeast by replenishing mitochondrial phosphatidylethanolamine.
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DOI：
10.1016/j.jbc.2021.100539
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Gohil VM
中科院分区：
文献类型：
--
作者：
Iadarola DM;Joshi A;Caldwell CB;Gohil VM
磷脂酰乙醇胺(PE)是酵母线粒体呼吸所必需的，而最丰富的线粒体磷脂磷脂酰胆碱(PC)在很大程度上是必不可少的。令人惊讶的是，胆碱(Cho)是PC的生物合成前体，已被证明可以拯救线粒体PE缺陷酵母的呼吸生长；然而，这种拯救的机制尚不清楚。结合酵母遗传学、脂质生物化学和细胞生物学方法，我们揭示了CHO通过部分补充缺乏线粒体PE生物合成酶Psd1的酵母细胞的线粒体PE水平来挽救线粒体呼吸的机制。这种拯救依赖于CHO通过肯尼迪途径转化为PC以及Psd2，Psd2是一种催化内体中PE生物合成的酶。代谢标记实验表明，在没有外源CHO的情况下，通过Psd2生物合成的PE主要指向PC生物合成的甲基化途径，而不能在Psd1缺失的细胞中补充线粒体PE。在这种情况下，通过CHO刺激肯尼迪途径合成PC，可以从甲基化途径中节省Psd2合成的PE，并将其重定向到线粒体。CHO介导的线粒体PE的升高依赖于Vps39，它最近被认为参与了PE向线粒体的运输。因此，上位性实验在基于CHO的救援中将Vps39放在Psd2的下游。因此，我们的工作提供了一种基于CHO的线粒体PE缺乏症的拯救机制，并揭示了维持线粒体PE动态平衡的复杂的细胞器间磷脂调节网络。
Phosphatidylethanolamine (PE) is essential for mitochondrial respiration in yeast, Saccharomyces cerevisiae, whereas the most abundant mitochondrial phospholipid, phosphatidylcholine (PC), is largely dispensable. Surprisingly, choline (Cho), which is a biosynthetic precursor of PC, has been shown to rescue the respiratory growth of mitochondrial PE-deficient yeast; however, the mechanism underlying this rescue has remained unknown. Using a combination of yeast genetics, lipid biochemistry, and cell biological approaches, we uncover the mechanism by showing that Cho rescues mitochondrial respiration by partially replenishing mitochondrial PE levels in yeast cells lacking the mitochondrial PE-biosynthetic enzyme Psd1. This rescue is dependent on the conversion of Cho to PC via the Kennedy pathway as well as on Psd2, an enzyme catalyzing PE biosynthesis in the endosome. Metabolic labeling experiments reveal that in the absence of exogenously supplied Cho, PE biosynthesized via Psd2 is mostly directed to the methylation pathway for PC biosynthesis and is unavailable for replenishing mitochondrial PE in Psd1-deleted cells. In this setting, stimulating the Kennedy pathway for PC biosynthesis by Cho spares Psd2-synthesized PE from the methylation pathway and redirects it to the mitochondria. Cho-mediated elevation in mitochondrial PE is dependent on Vps39, which has been recently implicated in PE trafficking to the mitochondria. Accordingly, epistasis experiments placed Vps39 downstream of Psd2 in Cho-based rescue. Our work, thus, provides a mechanism of Cho-based rescue of mitochondrial PE deficiency and uncovers an intricate interorganelle phospholipid regulatory network that maintains mitochondrial PE homeostasis.
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影响因子：
3.5
作者：
Basu Ball W;Neff JK;Gohil VM
通讯作者：
Gohil VM
影响因子：
3.3
作者：
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DOI：
10.1016/j.bbalip.2004.09.007
发表时间：
2004-11-08
影响因子：
4.8
作者：
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作者：
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