2. Academic Validation
  3. Mitofusin2 ameliorated ER stress and mitochondrial ROS through maintaining mitochondria-associated ER membrane integrity in cisplatin-induced acute kidney injury

Mitofusin2 ameliorated ER stress and mitochondrial ROS through maintaining mitochondria-associated ER membrane integrity in cisplatin-induced acute kidney injury

  • Antioxid Redox Signal. 2023 Apr 13. doi: 10.1089/ars.2022.0178.
Yu-Ting Liu 1,  Hao Zhang 2,  Shao-Bin Duan 3,  Jianwen Wang 4,  Hong Chen 5,  Ming Zhan 6,  Wei Zhang 7,  Ai-Mei Li 8,  Yan Liu 9,  Yang Yang 10,  Shikun Yang 11
Affiliations

Affiliations

  • 1 Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China; 208311026@csu.edu.cn.
  • 2 Central South University Third Xiangya Hospital, 504354, Nephrology, Changsha, China; zhanghaoliaoqing@163.com.
  • 3 Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China; duansb528@qq.com.
  • 4 Central South University Third Xiangya Hospital, 504354, Nephrology, Changsha, China; jwwangdoc@163.com.
  • 5 Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China; ch20165760806@163.com.
  • 6 International Medicine Department, Ningbo First Hospital, Zhejiang University, Ningbo, China; stephen0726@163.com.
  • 7 Central South University Third Xiangya Hospital, 504354, Nephrology, Yuelu district,Changsha City,Hunan Province,China, Changsha, China, 422000; weizhangxy@126.com.
  • 8 Department of Nephrology, The Third Xiangya Hospital, Central South University., Changsha, China; aimei_lam@163.com.
  • 9 Central South University Third Xiangya Hospital, 504354, Nephrology, Changsha, China; 42730339@qq.com.
  • 10 Department of Pneumology, The Third Xiangya Hospital, Central South University., Changsha, China; 7156392@qq.com.
  • 11 Central South University Third Xiangya Hospital, 504354, Nephrology, No.138, Tongzipo Road, Changsha, Hunan Province, China, Changsha, China, 410013; yangshikun@csu.edu.cn.
PMID: 37053105 DOI: 10.1089/ars.2022.0178
Abstract

Aims: This study investigated the regulatory effect of Mitofusin2 (Mfn2) on mitochondria-associated endoplasmic reticulum membrane (MAMs) integrity and cellular injury in cisplatin-induced acute kidney injury (CP-AKI).

Results: CP- AKI mice exhibited decreased expression of Mfn2, increased expression of phosphorylated adenosine monophosphate activated protein kinase (P-AMPK), abnormal mitochondrial morphology, and reduced MAMs integrity, accompanied by the activation of mitochondrial ROS and ER stress (IRE1 and PERK pathways). In in vitro studies, CP-induced mitochondrial ROS, ER stress activation, and increased Apoptosis were accompanied by the downregulation of Mfn2 and MAMs integrity reduction in Boston University mouse proximal tubular (BUMPT) cells and human proximal tubular epithelial (HK-2) cells. Pretreatment of BUMPT cells with the Mfn2 plasmid partially restored the integrity of MAMs, negatively controled IRE1 and PERK pathways, and inhibited cell Apoptosis. In contrast, ER stress and MAMs integrity violations were increased after Mfn2 siRNA treatment in HK-2 cells under CP treatment. Co-immunoprecipitation analysis demonstrated that Mfn2 interacted with PERK and IRE1. Furthermore, the AMPK agonist, AICAR had a similar effect like Mfn2 plasmid in the regulation of ER stress and MAMs. Conversely, the ER stress inhibitor, 4-PBA, had no effect on the expression of Mfn2 and MAMs integrity.

Innovation and conclusion: This is the first study to explore the association between MAMs, ER stress, and Mfn2 in CP-AKI. Downregulation of Mfn2 expression abolished the MAMs integrity and induced ER stress, mitochondrial ROS, and tubular cell Apoptosis. This suggests that the Mfn2-MAMs pathway is a potential therapeutic target in CP-AKI.

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