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人抗原 R 通过 PARKIN/BNIP3L 的表达调节肾小管细胞缺氧诱导的自噬。

Human antigen R regulates hypoxia-induced mitophagy in renal tubular cells through PARKIN/BNIP3L expressions.

机构信息

Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.

Department of Emergency Medicine, China Medical University Hospital, Taichung, Taiwan.

出版信息

J Cell Mol Med. 2021 Mar;25(5):2691-2702. doi: 10.1111/jcmm.16301. Epub 2021 Jan 26.

DOI:10.1111/jcmm.16301
PMID:33496385
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7933924/
Abstract

Mitochondrial dysfunction contributes to the pathophysiology of acute kidney injury (AKI). Mitophagy selectively degrades damaged mitochondria and thereby regulates cellular homeostasis. RNA-binding proteins (RBPs) regulate RNA processing at multiple levels and thereby control cellular function. In this study, we aimed to understand the role of human antigen R (HuR) in hypoxia-induced mitophagy process in the renal tubular cells. Mitophagy marker expressions (PARKIN, p-PARKIN, PINK1, BNIP3L, BNIP3, LC3) were determined by western blot analysis. Immunofluorescence studies were performed to analyze mitophagosome, mitolysosome, co-localization of p-PARKIN/TOMM20 and BNIP3L/TOMM20. HuR-mediated regulation of PARKIN/BNIP3L expressions was determined by RNA-immunoprecipitation analysis and RNA stability experiments. Hypoxia induced mitochondrial dysfunction by increased ROS, decline in membrane potential and activated mitophagy through up-regulated PARKIN, PINK1, BNIP3 and BNIP3L expressions. HuR knockdown studies revealed that HuR regulates hypoxia-induced mitophagosome and mitolysosome formation. HuR was significantly bound to PARKIN and BNIP3L mRNA under hypoxia and thereby up-regulated their expressions through mRNA stability. Altogether, our data highlight the importance of HuR in mitophagy regulation through up-regulating PARKIN/BNIP3L expressions in renal tubular cells.

摘要

线粒体功能障碍导致急性肾损伤 (AKI) 的病理生理学变化。自噬选择性地降解受损的线粒体，从而调节细胞内稳态。RNA 结合蛋白 (RBPs) 在多个水平上调节 RNA 加工，从而控制细胞功能。在这项研究中，我们旨在了解人类抗原 R (HuR) 在肾小管细胞缺氧诱导的自噬过程中的作用。通过 Western blot 分析测定自噬标志物的表达（PARKIN、p-PARKIN、PINK1、BNIP3L、BNIP3、LC3）。通过免疫荧光研究分析自噬体、自噬溶酶体、p-PARKIN/TOMM20 和 BNIP3L/TOMM20 的共定位。通过 RNA-免疫沉淀分析和 RNA 稳定性实验确定 HuR 对 PARKIN/BNIP3L 表达的调节作用。缺氧通过增加 ROS、膜电位下降和上调 PARKIN、PINK1、BNIP3 和 BNIP3L 的表达来诱导线粒体功能障碍，从而激活自噬。HuR 敲低研究表明 HuR 调节缺氧诱导的自噬体和自噬溶酶体的形成。在缺氧下，HuR 与 PARKIN 和 BNIP3L mRNA 结合明显，并通过 mRNA 稳定性上调其表达。总之，我们的数据强调了 HuR 通过上调肾小管细胞中 PARKIN/BNIP3L 的表达在自噬调节中的重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdae/7933924/7802d301c483/JCMM-25-2691-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdae/7933924/ba19053f3d20/JCMM-25-2691-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdae/7933924/5ba009059818/JCMM-25-2691-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdae/7933924/c792a6a551a9/JCMM-25-2691-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdae/7933924/7802d301c483/JCMM-25-2691-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdae/7933924/ba19053f3d20/JCMM-25-2691-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdae/7933924/027ec405cb8b/JCMM-25-2691-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdae/7933924/8da4806dc38e/JCMM-25-2691-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdae/7933924/005f71f438f7/JCMM-25-2691-g004.jpg
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