Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
J Biol Chem. 2012 Nov 23;287(48):40131-9. doi: 10.1074/jbc.M112.399428. Epub 2012 Oct 8.
Phosphatidylethanolamine is proposed to regulate mitochondrial fusion, but its mechanism of action is unknown.
Decreasing phosphatidylethanolamine reduces the rate of lipid mixing and the biogenesis of Mgm1, a mitochondrial fusion protein.
Psd1 regulates the lipid and protein machineries of mitochondrial fusion.
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 Δpsd1 strain could be due to the altered biophysical properties of the mitochondrial membrane, resulting in reduced fusion kinetics. The Δpsd1 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 Δpsd1 strain. Increasing s-Mgm1 levels in Δpsd1 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.
磷脂酰乙醇胺被提议调节线粒体融合，但它的作用机制尚不清楚。
减少磷脂酰乙醇胺会降低脂质混合的速率和 Mgm1 的生物发生，Mgm1 是一种线粒体融合蛋白。
Psd1 调节线粒体融合的脂质和蛋白质机制。
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。非双层形成的脂质，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知之甚少。在这里，我们表明，定位于线粒体的 Psd1 是合成 PE 的关键酵母酶，对于适当的线粒体形态和融合是必需的。缺乏 Psd1 的酵母细胞表现出线粒体碎片化和聚集，在交配过程中线粒体融合受损。更重要的是，我们证明 PE 的减少降低了脂质混合的速率，在反映线粒体膜的脂质组成的脂质体融合过程中。这表明 Δpsd1 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性质发生改变，导致融合动力学降低。Δpsd1 菌株还表现出线粒体活性（如氧化磷酸化）受损和线粒体 ATP 水平降低，这是由于线粒体 PE 减少所致。Psd1 的缺失也会损害 s-Mgm1 的生物发生，s-Mgm1 是线粒体融合所必需的蛋白质，这进一步加剧了 Δpsd1 菌株的线粒体融合缺陷。在 Δpsd1 细胞中增加 s-Mgm1 的水平显著减少了线粒体聚集。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。虽然有几种蛋白质需要协调膜融合的复杂过程，但我们提出，线粒体膜的特定磷脂通过增强脂质混合动力学和调节促融合蛋白的作用来促进融合。
