Seipin regulates lipid homeostasis by ensuring calcium-dependent mitochondrial metabolism
Seipin regulates lipid homeostasis by ensuring calcium-dependent mitochondrial metabolism
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Seipin 通过确保钙依赖性线粒体代谢来调节脂质稳态
DOI：
10.15252/embj.201797572
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发表时间：
2018-09-03
期刊：
影响因子：
11.4
通讯作者：
Huang, Xun
中科院分区：
文献类型：
--
作者：
Ding, Long;Yang, Xiao;Huang, Xun
Seipin是导致Berardinelli-Seip先天性脂肪营养不良2型（BSCL 2）的基因，对脂肪细胞分化和脂质稳态很重要。以往的研究表明，在果蝇Seipin促进内质网钙稳态通过Ca 2 +-ATP酶SERCA，但很少有人知道的事件下游的扰动内质网钙稳态，导致减少脂质储存在果蝇dSeipin突变体。在这里，我们表明，糖酵解代谢产物积累和下游线粒体TCA循环受损dSeipin突变体。受损的TCA循环进一步导致柠檬酸盐水平降低，柠檬酸盐是脂肪生成的关键组分。在机制上，Seipin/SERCA介导的ER钙稳态对于维持线粒体钙稳态是重要的。dSeipin突变体中线粒体钙的减少影响TCA循环和线粒体功能。dSeipin突变脂肪细胞中的脂质储存缺陷可以通过补充线粒体钙或通过遗传操作或补充外源性代谢物恢复柠檬酸盐水平来挽救。总之，我们的研究结果表明，Seipin通过钙依赖性线粒体代谢促进脂肪组织脂质储存。
Seipin, the gene that causes Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), is important for adipocyte differentiation and lipid homeostasis. Previous studies in Drosophila revealed that Seipin promotes ER calcium homeostasis through the Ca2+-ATPase SERCA, but little is known about the events downstream of perturbed ER calcium homeostasis that lead to decreased lipid storage in Drosophila dSeipin mutants. Here, we show that glycolytic metabolites accumulate and the downstream mitochondrial TCA cycle is impaired in dSeipin mutants. The impaired TCA cycle further leads to a decreased level of citrate, a critical component of lipogenesis. Mechanistically, Seipin/SERCA-mediated ER calcium homeostasis is important for maintaining mitochondrial calcium homeostasis. Reduced mitochondrial calcium in dSeipin mutants affects the TCA cycle and mitochondrial function. The lipid storage defects in dSeipin mutant fat cells can be rescued by replenishing mitochondrial calcium or by restoring the level of citrate through genetic manipulations or supplementation with exogenous metabolites. Together, our results reveal that Seipin promotes adipose tissue lipid storage via calcium-dependent mitochondrial metabolism.