磷脂酰丝氨酸脱羧酶 1 (Psd1) 通过调节线粒体膜的生物物理特性和线粒体基因组维持蛋白 1 (Mgm1) 的替代拓扑生成来促进线粒体融合。,Journal of Biological Chemistry

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磷脂酰丝氨酸脱羧酶 1 (Psd1) 通过调节线粒体膜的生物物理特性和线粒体基因组维持蛋白 1 (Mgm1) 的替代拓扑生成来促进线粒体融合。
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2012 Nov 23 , DOI: 10.1074/jbc.m112.399428
Eliana Y L Chan ₁ , G Angus McQuibban

Affiliation

背景：磷脂酰乙醇胺被提议用于调节线粒体融合，但其作用机制尚不清楚。结果：减少磷脂酰乙醇胺会降低脂质混合率和线粒体融合蛋白 Mgm1 的生物发生。结论：Psd1 调节线粒体融合的脂质和蛋白质机制。意义：了解脂质代谢如何调节线粒体动力学将揭示其在细胞功能如细胞凋亡和自噬中的作用。非双层形成脂质如心磷脂、磷脂酸和磷脂酰乙醇胺 (PE) 被提议产生负膜曲率，促进膜融合。然而，脂质调节线粒体融合的机制仍然知之甚少。在这里，我们展示了线粒体定位的 Psd1，合成 PE 的关键酵母酶是适当的线粒体形态和融合所必需的。缺乏 Psd1 的酵母细胞在交配过程中表现出分裂和聚集的线粒体，线粒体融合受损。更重要的是，我们证明了在脂质体与反映线粒体膜的脂质组合物融合过程中，PE 的减少降低了脂质混合的速率。这表明 Deltapsd1 菌株中的线粒体融合缺陷可能是由于线粒体膜的生物物理特性改变，导致融合动力学降低。Deltapsd1 菌株的线粒体活性也受损，如氧化磷酸化和线粒体 ATP 水平降低，这是由于线粒体 PE 的减少。Psd1 的缺失也会损害 s-Mgm1 的生物发生，线粒体融合所必需的蛋白质，进一步加剧了 Deltapsd1 菌株的线粒体融合缺陷。增加 Deltapsd1 细胞中的 s-Mgm1 水平显着减少了线粒体聚集。我们的结果表明，线粒体 PE 通过调节线粒体膜的生物物理特性和增强 s-Mgm1 的生物发生来调节线粒体融合。虽然需要几种蛋白质来协调膜融合的复杂过程，但我们建议线粒体膜的特定磷脂通过增强脂质混合动力学和调节大量蛋白质的作用来促进融合。我们的结果表明，线粒体 PE 通过调节线粒体膜的生物物理特性和增强 s-Mgm1 的生物发生来调节线粒体融合。虽然需要几种蛋白质来协调膜融合的复杂过程，但我们建议线粒体膜的特定磷脂通过增强脂质混合动力学和调节大量蛋白质的作用来促进融合。我们的结果表明，线粒体 PE 通过调节线粒体膜的生物物理特性和增强 s-Mgm1 的生物发生来调节线粒体融合。虽然需要几种蛋白质来协调膜融合的复杂过程，但我们建议线粒体膜的特定磷脂通过增强脂质混合动力学和调节大量蛋白质的作用来促进融合。

"点击查看英文标题和摘要"

Phosphatidylserine decarboxylase 1 (Psd1) promotes mitochondrial fusion by regulating the biophysical properties of the mitochondrial membrane and alternative topogenesis of mitochondrial genome maintenance protein 1 (Mgm1).

BACKGROUND: Phosphatidylethanolamine is proposed to regulate mitochondrial fusion, but its mechanism of action is unknown. RESULTS: Decreasing phosphatidylethanolamine reduces the rate of lipid mixing and the biogenesis of Mgm1, a mitochondrial fusion protein. CONCLUSION: Psd1 regulates the lipid and protein machineries of mitochondrial fusion. SIGNIFICANCE: Understanding how lipid metabolism regulates mitochondrial dynamics will reveal its role in cellular functions such as apoptosis and autophagy. Non-bilayer-forming lipids such as cardiolipin, phosphatidic acid, and phosphatidylethanolamine (PE) are proposed to generate negative membrane curvature, promoting membrane fusion. However, the mechanism by which lipids regulate mitochondrial fusion remains poorly understood. Here, we show that mitochondrial-localized Psd1, the key yeast enzyme that synthesizes PE, is required for proper mitochondrial morphology and fusion. Yeast cells lacking Psd1 exhibit fragmented and aggregated mitochondria with impaired mitochondrial fusion during mating. More importantly, we demonstrate that a reduction in PE reduces the rate of lipid mixing during fusion of liposomes with lipid compositions reflecting the mitochondrial membrane. This suggests that the mitochondrial fusion defect in the Deltapsd1 strain could be due to the altered biophysical properties of the mitochondrial membrane, resulting in reduced fusion kinetics. The Deltapsd1 strain also has impaired mitochondrial activity such as oxidative phosphorylation and reduced mitochondrial ATP levels which are due to a reduction in mitochondrial PE. The loss of Psd1 also impairs the biogenesis of s-Mgm1, a protein essential for mitochondrial fusion, further exacerbating the mitochondrial fusion defect of the Deltapsd1 strain. Increasing s-Mgm1 levels in Deltapsd1 cells markedly reduced mitochondrial aggregation. Our results demonstrate that mitochondrial PE regulates mitochondrial fusion by regulating the biophysical properties of the mitochondrial membrane and by enhancing the biogenesis of s-Mgm1. While several proteins are required to orchestrate the intricate process of membrane fusion, we propose that specific phospholipids of the mitochondrial membrane promote fusion by enhancing lipid mixing kinetics and by regulating the action of profusion proteins.

更新日期：2017-01-31

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