Cargando…
NLRX1/FUNDC1/NIPSNAP1‐2 axis regulates mitophagy and alleviates intestinal ischaemia/reperfusion injury
OBJECTIVES: Mitophagy is considered to be a key mechanism in the pathogenesis of intestinal ischaemic reperfusion (IR) injury. NOD‐like receptor X1 (NLRX1) is located in the mitochondria and is highly expressed in the intestine, and is known to modulate ROS production, mitochondrial damage, autophag...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941235/ https://www.ncbi.nlm.nih.gov/pubmed/33432610 http://dx.doi.org/10.1111/cpr.12986 |
_version_ | 1783662114658844672 |
---|---|
author | Li, Shaoqin Zhou, Yi Gu, Xiaocheng Zhang, Xiaoping Jia, Zhongzhi |
author_facet | Li, Shaoqin Zhou, Yi Gu, Xiaocheng Zhang, Xiaoping Jia, Zhongzhi |
author_sort | Li, Shaoqin |
collection | PubMed |
description | OBJECTIVES: Mitophagy is considered to be a key mechanism in the pathogenesis of intestinal ischaemic reperfusion (IR) injury. NOD‐like receptor X1 (NLRX1) is located in the mitochondria and is highly expressed in the intestine, and is known to modulate ROS production, mitochondrial damage, autophagy and apoptosis. However, the function of NLRX1 in intestinal IR injury is unclear. MATERIALS AND METHODS: NLRX1 in rats with IR injury or in IEC‐6 cells with hypoxia reoxygenation (HR) injury were measured by Western blotting, real‐time PCR and immunohistochemistry. The function of NLRX1‐FUNDC1‐NIPSNAP1/NIPSNAP2 axis in mitochondrial homeostasis and cell apoptosis were assessed in vitro. RESULTS: NLRX1 is significantly downregulated following intestinal IR injury. In vivo studies showed that rats overexpressing NLRX1 exhibited resistance against intestinal IR injury and mitochondrial dysfunction. These beneficial effects of NLRX1 overexpression were dependent on mitophagy activation. Functional studies showed that HR injury reduced NLRX1 expression, which promoted phosphorylation of FUN14 domain‐containing 1 (FUNDC1). Based on immunoprecipitation studies, it was evident that phosphorylated FUNDC1 could not interact with the mitophagy signalling proteins NIPSNAP1 and NIPSNAP2 on the outer membrane of damaged mitochondria, which failed to launch the mitophagy process, resulting in the accumulation of damaged mitochondria and epithelial apoptosis. CONCLUSIONS: NLRX1 regulates mitophagy via FUNDC1‐NIPSNAP1/NIPSNAP2 signalling pathway. Thus, this study provides a potential target for the development of a therapeutic strategy for intestinal IR injury. |
format | Online Article Text |
id | pubmed-7941235 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-79412352021-03-16 NLRX1/FUNDC1/NIPSNAP1‐2 axis regulates mitophagy and alleviates intestinal ischaemia/reperfusion injury Li, Shaoqin Zhou, Yi Gu, Xiaocheng Zhang, Xiaoping Jia, Zhongzhi Cell Prolif Original Articles OBJECTIVES: Mitophagy is considered to be a key mechanism in the pathogenesis of intestinal ischaemic reperfusion (IR) injury. NOD‐like receptor X1 (NLRX1) is located in the mitochondria and is highly expressed in the intestine, and is known to modulate ROS production, mitochondrial damage, autophagy and apoptosis. However, the function of NLRX1 in intestinal IR injury is unclear. MATERIALS AND METHODS: NLRX1 in rats with IR injury or in IEC‐6 cells with hypoxia reoxygenation (HR) injury were measured by Western blotting, real‐time PCR and immunohistochemistry. The function of NLRX1‐FUNDC1‐NIPSNAP1/NIPSNAP2 axis in mitochondrial homeostasis and cell apoptosis were assessed in vitro. RESULTS: NLRX1 is significantly downregulated following intestinal IR injury. In vivo studies showed that rats overexpressing NLRX1 exhibited resistance against intestinal IR injury and mitochondrial dysfunction. These beneficial effects of NLRX1 overexpression were dependent on mitophagy activation. Functional studies showed that HR injury reduced NLRX1 expression, which promoted phosphorylation of FUN14 domain‐containing 1 (FUNDC1). Based on immunoprecipitation studies, it was evident that phosphorylated FUNDC1 could not interact with the mitophagy signalling proteins NIPSNAP1 and NIPSNAP2 on the outer membrane of damaged mitochondria, which failed to launch the mitophagy process, resulting in the accumulation of damaged mitochondria and epithelial apoptosis. CONCLUSIONS: NLRX1 regulates mitophagy via FUNDC1‐NIPSNAP1/NIPSNAP2 signalling pathway. Thus, this study provides a potential target for the development of a therapeutic strategy for intestinal IR injury. John Wiley and Sons Inc. 2021-01-11 /pmc/articles/PMC7941235/ /pubmed/33432610 http://dx.doi.org/10.1111/cpr.12986 Text en © 2021 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Li, Shaoqin Zhou, Yi Gu, Xiaocheng Zhang, Xiaoping Jia, Zhongzhi NLRX1/FUNDC1/NIPSNAP1‐2 axis regulates mitophagy and alleviates intestinal ischaemia/reperfusion injury |
title | NLRX1/FUNDC1/NIPSNAP1‐2 axis regulates mitophagy and alleviates intestinal ischaemia/reperfusion injury |
title_full | NLRX1/FUNDC1/NIPSNAP1‐2 axis regulates mitophagy and alleviates intestinal ischaemia/reperfusion injury |
title_fullStr | NLRX1/FUNDC1/NIPSNAP1‐2 axis regulates mitophagy and alleviates intestinal ischaemia/reperfusion injury |
title_full_unstemmed | NLRX1/FUNDC1/NIPSNAP1‐2 axis regulates mitophagy and alleviates intestinal ischaemia/reperfusion injury |
title_short | NLRX1/FUNDC1/NIPSNAP1‐2 axis regulates mitophagy and alleviates intestinal ischaemia/reperfusion injury |
title_sort | nlrx1/fundc1/nipsnap1‐2 axis regulates mitophagy and alleviates intestinal ischaemia/reperfusion injury |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941235/ https://www.ncbi.nlm.nih.gov/pubmed/33432610 http://dx.doi.org/10.1111/cpr.12986 |
work_keys_str_mv | AT lishaoqin nlrx1fundc1nipsnap12axisregulatesmitophagyandalleviatesintestinalischaemiareperfusioninjury AT zhouyi nlrx1fundc1nipsnap12axisregulatesmitophagyandalleviatesintestinalischaemiareperfusioninjury AT guxiaocheng nlrx1fundc1nipsnap12axisregulatesmitophagyandalleviatesintestinalischaemiareperfusioninjury AT zhangxiaoping nlrx1fundc1nipsnap12axisregulatesmitophagyandalleviatesintestinalischaemiareperfusioninjury AT jiazhongzhi nlrx1fundc1nipsnap12axisregulatesmitophagyandalleviatesintestinalischaemiareperfusioninjury |