Sphingosine kinase 1 overexpression induces MFN2 fragmentation and alters mitochondrial matrix Ca2+ handling in HeLa cells.
Sphingosine kinase 1 overexpression induces MFN2 fragmentation and alters mitochondrial matrix Ca2+ handling in HeLa cells.
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DOI：
10.1016/j.bbamcr.2019.06.006
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发表时间：
2019-09
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通讯作者：
I. Pulli;C. Löf;T. Blom;T. Blom;Muhammad Yasir Asghar;Muhammad Yasir Asghar;Taru Lassila;Taru Lassila;Nils Bäck;K-L Lin;J. Nyström;Kati Kemppainen;Diana M. Toivola;Eric Dufour;Alberto Sanz;Helen M. Cooper;J. Parys;K. Törnquist;K. Törnquist
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作者：
I. Pulli;C. Löf;T. Blom;T. Blom;Muhammad Yasir Asghar;Muhammad Yasir Asghar;Taru Lassila;Taru Lassila;Nils Bäck;K-L Lin;J. Nyström;Kati Kemppainen;Diana M. Toivola;Eric Dufour;Alberto Sanz;Helen M. Cooper;J. Parys;K. Törnquist;K. Törnquist
鞘氨醇激酶1(SK1)将鞘氨醇转化为具有生物活性的磷脂鞘氨醇1磷酸(S1P)。S1P与G蛋白偶联受体(S1PR1-5)结合，调节细胞事件，包括钙信号。SK1/S1P轴和钙信号在健康和疾病中都发挥着重要的作用。在这方面，线粒体相关内质网(ER)膜(MAM)上的钙微域在肿瘤发生中起着重要作用。丝裂原蛋白2(Mitofusin 2，Mfn2)调节内质网-线粒体的接触，Mfn2的异常调节与恶性肿瘤有关。我们发现，SK1的过表达增加了激动剂诱导的内质网钙释放，导致线粒体基质钙离子增加。此外，SK1的过表达诱导Mfn2片段化，可能是通过增加钙蛋白酶的活性。此外，在激动剂刺激过程中，表达可能被Calain裂解的Mfn2N-末端和C-末端片段会增加线粒体基质钙离子，类似于SK1在细胞中的过表达。此外，SK1的过表达增强了细胞的呼吸和细胞迁移。因此，SK1调节Mfn2的断裂，导致线粒体钙离子增加和下游细胞效应。
Sphingosine kinase 1 (SK1) converts sphingosine to the bioactive lipid sphingosine 1-phosphate (S1P). S1P binds to G-protein-coupled receptors (S1PR1–5) to regulate cellular events, including Ca2+signaling. The SK1/S1P axis and Ca2+signaling both play important roles in health and disease. In this respect, Ca2+microdomains at the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are of importance in oncogenesis. Mitofusin 2 (MFN2) modulates ER-mitochondria contacts, and dysregulation of MFN2 is associated with malignancies. We show that overexpression of SK1 augments agonist-induced Ca2+release from the ER resulting in increased mitochondrial matrix Ca2+. Also, overexpression of SK1 induces MFN2 fragmentation, likely through increased calpain activity. Further, expressing putative calpain-cleaved MFN2 N- and C-terminal fragments increases mitochondrial matrix Ca2+during agonist stimulation, mimicking the SK1 overexpression in cells. Moreover, SK1 overexpression enhances cellular respiration and cell migration. Thus, SK1 regulates MFN2 fragmentation resulting in increased mitochondrial Ca2+and downstream cellular effects.