Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway

作者：Yun Cao, Zhaowei Chen, Jijia Hu, Jun Feng, Zijing Zhu, Yanqin Fan, Qiaoxuan Lin, Guohua Ding · 发表于：Frontiers in Cell and Developmental Biology · 年份：2021 · DOI：10.3389/fcell.2021.769213 · 被引用次数：100 · 研究领域：Mitochondrial Function and Pathology、Endoplasmic Reticulum Stress and Disease、Autophagy in Disease and Therapy

The endoplasmic reticulum (ER) stress and mitochondrial dysfunction in high glucose (HG)-induced podocyte injury have been demonstrated to the progression of diabetic kidney disease (DKD). However, the pathological mechanisms remain equivocal. Mitofusin2 (Mfn2) was initially identified as a dynamin-like protein involved in fusing the outer mitochondrial membrane (OMM). More recently, Mfn2 has been reported to be located at the ER membranes that contact OMM. Mitochondria-associated ER membranes (MAMs) is the intercellular membrane subdomain, which connects the mitochondria and ER through a proteinaceous tether. Here, we observed the suppression of Mfn2 expression in the glomeruli and glomerular podocytes of patients with DKD. Streptozotocin (STZ)-induced diabetic rats exhibited abnormal mitochondrial morphology and MAMs reduction in podocytes, accompanied by decreased expression of Mfn2 and activation of all three unfolded protein response (UPR) pathways (IRE1, ATF6, and PERK). The HG-induced mitochondrial dysfunction, MAMs reduction, and increased apoptosis in vitro were accompanied by the downregulation of Mfn2 and activation of the PERK pathway. Mfn2 physically interacts with PERK, and HG promotes a decrease in Mfn2-PERK interaction. In addition, Mfn2-silenced podocytes showed mitochondrial dysfunction, MAMs reduction, activation of PERK pathway, and increased apoptosis. Conversely, all these effects of HG stimulation were alleviated significantly by Mfn2 overexpression. Fu...