Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 21, 2020; 26(15): 1758-1774
Published online Apr 21, 2020. doi: 10.3748/wjg.v26.i15.1758
PTEN-induced kinase 1-induced dynamin-related protein 1 Ser637 phosphorylation reduces mitochondrial fission and protects against intestinal ischemia reperfusion injury
Wasim Qasim, Yang Li, Rui-Min Sun, Dong-Cheng Feng, Zhan-Yu Wang, De-Shun Liu, Ji-Hong Yao, Xiao-Feng Tian
Wasim Qasim, Yang Li, Dong-Cheng Feng, Zhan-Yu Wang, De-Shun Liu, Xiao-Feng Tian, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
Yang Li, Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
Rui-Min Sun, Ji-Hong Yao, Department of Pharmacology, Dalian Medical University, Dalian 116044, Liaoning Province, China
Author contributions: Qasim W, Li Y and Sun RM contributed equally to the present study; Qasim W, Li Y, Sun RM, Feng DC, Wang ZY, and Liu DS performed the experiments and analyzed the data; Qasim W, Li Y and Sun RM wrote the article; Yao JH and Tian XF designed the experiments, revised the article, and obtained research funding; all authors approved the final version of the article.
Supported by the National Natural Science Foundation of China, No. 81679154, No. 81871547.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board at Dalian Medical University.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Dalian Medical University.
Conflict-of-interest statement: All the authors have nothing to disclose.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Xiao-Feng Tian, MD, PhD, Director, Professor, Surgeon, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Shahekou District, Dalian 116023, Liaoning Province, China.
Received: December 28, 2019
Peer-review started: December 28, 2019
First decision: January 11, 2020
Revised: March 17, 2020
Accepted: March 27, 2020
Article in press: March 27, 2020
Published online: April 21, 2020
Research background

PTEN-induced putative kinase (PINK1) is a novel regulator of mitochondrial homeostasis that phosphorylates target proteins in mitochondria. PINK1 depletion has been identified to be related to mitochondrial fragmentation, ROS accumulation and apoptosis. However, the underlying regulatory mechanism of PINK1 in intestinal ischemia reperfusion (I/R) injury remains unclear. Therefore, elucidation of the protective role of PINK1 may help to improve tissue repair in I/R injury.

Research motivation

It is necessary to explore the function and target of PINK1 in mitochondrial regulation in intestinal I/R injury. Previous studies have demonstrated that mitochondrial dysfunction-induced apoptosis is an important cause of intestinal mucosal barrier damage and is associated with a high mortality rate in clinical practice. Moreover, the role of PINK1 in the protection against ischemic diseases has been clarified. These findings provide a basis for further study regarding the mechanism and target of PINK1 during intestinal I/R injury.

Research objectives

In a previous study, we investigated the effect of PINK1 on mitochondrial fission after intestinal I/R injury both in vivo and in vitro by gain- and loss-of-function approaches. Furthermore, we explored the phosphorylation site of DRP1, which is a downstream target of PINK1. Our study provides significant insight into the signaling mechanism of PINK1 during intestinal I/R injury and may contribute to the future investigation of more effective therapies in clinical practice.

Research methods

Experiments used an in vivo mouse model and an in vitro Caco-2 cells models to better elucidate the pathophysiological process of intestinal I/R injury. Hematoxylin and eosin staining, and Chiu’s scoring system were used to demonstrate intestinal tissue injury. TUNEL and mitoSOX staining was carried out to display and observe apoptotic cells and ROS accumulation. Gene silencing and transfection were conducted to construct PINK1-depleted or PINK1-overexpressing cells to complete functional studies in vitro. A series of in vitro experiments, such as Western blotting, Cell Counting Kit-8 assays, and MitoTracker staining, were performed to explore the effect of PINK1 on mitochondrial fission.

Research results

Experiments in vivo showed the correlation between PINK1 and mucosal injury after intestinal I/R injury. The results of in vitro experiments showed a direct positive correlation of PINK1 with mitochondrial protection and apoptosis inhibition after hypoxia/reoxygenation. This study could be valuable as a basis for further studies on intestinal I/R injury and could potentially be utilized for therapeutic enhancement in clinical practice. Some limitations did exist: The in vivo study should be better designed to clarify causation and biological linkage, and PINK1 knockout mouse models would be helpful. Clinical samples are also needed to better support the application to human beings.

Research conclusions

PINK1 plays a positive role in mitochondrial homeostasis and apoptosis inhibition in intestinal I/R injury. This study reveals that PINK1 could improve the phosphorylation of DRP1 at Ser637. Targeting the PINK1/DRP1 pathway may increase the therapeutic potential for intestinal I/R injury in clinical practice.

Research perspectives

Our study illuminates the role of PINK1 in mitochondrial protection in intestinal I/R injury. Other researchers have reported that PINK1 is associated with mitophagy under I/R stress. Thus, the link between PINK1 and mitophagy in intestinal I/R needs further investigation.