Seipin regulates lipid homeostasis by ensuring calcium‐dependent mitochondrial metabolism |
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| Authors: | Long Ding Xiao Yang He Tian Jingjing Liang Fengxia Zhang Guodong Wang Yingchun Wang Mei Ding Guanghou Shui Xun Huang |
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| Affiliation: | 1. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China;2. University of Chinese Academy of Sciences, Beijing, China;3. State Key Laboratory of Plant Genomics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China |
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| Abstract: | 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. |
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| Keywords: | calcium lipid storage metabolism mitochondrion Seipin |
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