AKAP1 mediates high glucose-induced mitochondrial fission through the phosphorylation of Drp1 in podocytes
AKAP1 mediates high glucose-induced mitochondrial fission through the phosphorylation of Drp1 in podocytes
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AKAP1 通过足细胞中 Drp1 的磷酸化介导高糖诱导的线粒体分裂
DOI：
10.1002/jcp.29646
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发表时间：
2020-02-28
影响因子：
5.6
通讯作者：
Ding, Guohua
中科院分区：
文献类型：
--
作者：
Chen, Zhaowei;Ma, Yiqiong;Ding, Guohua
越来越多的证据表明，线粒体功能障碍在糖尿病肾病（DKD）的发生发展中起着重要作用，但其具体的病理机制尚不清楚。A-激酶锚定蛋白（AKAP）1是AKAP家族中的支架蛋白，参与线粒体分裂和融合。在这里，我们表明，大鼠与链脲佐菌素（STZ）诱导的糖尿病发展足细胞损伤伴随AKAP 1过表达，AKAP 1密切相互作用的线粒体分裂酶动力相关蛋白1（Drp 1）。在分子水平上，高糖（HG）促进足细胞损伤和Drp1的Ser637磷酸化，如线粒体膜电位降低，活性氧产生增加，减少腺苷三磷酸合成，并增加足细胞凋亡证明。此外，AKAP 1敲低保护HG诱导的足细胞损伤，并抑制HG诱导的Drp1在Ser637的磷酸化。AKAP 1过表达加重HG诱导的线粒体断裂和足细胞凋亡。免疫共沉淀实验表明HG诱导的Drp1与AKAP 1相互作用，揭示了AKAP 1在HG刺激下可以从细胞质中募集Drp1。随后，我们通过转移几种不同的Drp1突变体来检测Drp1磷酸化对Ser637的影响。我们证明，激活AKAP 1促进Drp1在Ser637的磷酸化，这促进了Drp1转座到线粒体表面，并导致线粒体功能障碍事件。这些结果表明，AKAP 1是主要的致病因素，在汞诱导的足细胞损伤的发展和进展，通过破坏线粒体动态平衡，通过调节人足细胞中的Drp1磷酸化。
Increasing evidence suggests that mitochondrial dysfunction plays a critical role in the development of diabetic kidney disease (DKD), however, its specific pathomechanism remains unclear. A-kinase anchoring protein (AKAP) 1 is a scaffold protein in the AKAP family that is involved in mitochondrial fission and fusion. Here, we show that rats with streptozotocin (STZ)-induced diabetes developed podocyte damage accompanied by AKAP1 overexpression and that AKAP1 closely interacted with the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). At the molecular level, high glucose (HG) promoted podocyte injury and Drp1 phosphorylation at Ser637 as proven by decreased mitochondrial membrane potential, elevated reactive oxygen species generation, reduced adenosine triphosphate synthesis, and increased podocyte apoptosis. Furthermore, the AKAP1 knockdown protected HG-induced podocyte injury and suppressed HG-induced Drp1 phosphorylation at Ser637. AKAP1 overexpression aggravated HG-induced mitochondrial fragmentation and podocyte apoptosis. The coimmunoprecipitation assay showed that HG-induced Drp1 interacted with AKAP1, revealing that AKAP1 could recruit Drp1 from the cytoplasm under HG stimulation. Subsequently, we detected the effect of drp1 phosphorylation on Ser637 by transferring several different Drp1 mutants. We demonstrated that activated AKAP1 promoted Drp1 phosphorylation at Ser637, which promoted the transposition of Drp1 to the surface of the mitochondria and accounts for mitochondrial dysfunction events. These findings indicate that AKAP1 is the main pathogenic factor in the development and progression of HG-induced podocyte injury through the destruction of mitochondrial dynamic homeostasis by regulating Drp1 phosphorylation in human podocytes.