1. Academic Validation
  2. piR-823 inhibits cell apoptosis via modulating mitophagy by binding to PINK1 in colorectal cancer

piR-823 inhibits cell apoptosis via modulating mitophagy by binding to PINK1 in colorectal cancer

  • Cell Death Dis. 2022 May 17;13(5):465. doi: 10.1038/s41419-022-04922-6.
Shuling Wang  # 1 Xiaoyu Jiang  # 1 Xiaoli Xie 1 Jie Yin 1 Jiuna Zhang 1 Ting Liu 1 Shujia Chen 2 Yijun Wang 1 Xue Zhou 1 Yongjuan Wang 1 Ruolin Cui 1 Huiqing Jiang 3
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China.
  • 2 Department of Gastroenterology, Shijiazhuang People's Hospital, Shijiazhuang, 050000, Hebei, China.
  • 3 Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases, Shijiazhuang, Hebei, China. jianghq@aliyun.com.
  • # Contributed equally.
Abstract

Mitophagy plays a vital role in the maintenance of mitochondrial homeostasis and tumorigenesis. Noncoding RNA piR-823 contributes to colorectal tumorigenesis. In this study, we aim to evaluate piR-823-mediated Mitophagy and its mechanistic association with colorectal Cancer (CRC). Digital gene expression analysis was performed to explore the potential functions of piR-823. A piR-823 antagomir (Ant-823) was used to inhibit piR-823 expression, and piR-823 mimics (mimics-823) were used to increase piR-823 expression. Mitophagy was measured in vivo and in vitro by immunofluorescence and western blot analysis. JC-1 staining, ATP production, Real-Time PCR, and western blot analysis were used to measure changes in mitochondrial quality and number. siRNA transfection was used to inhibit Mitophagy, and CCCP was used to induce Mitophagy. RNA pull-down assays and RNA-binding protein immunoprecipitation assays were conducted to investigate the molecular mechanisms. Here, we found that CRC cells transfected with Ant-823 presented an altered expression of autophagic and Mitophagy genes by Digital gene expression analysis. Ant-823 could promote Parkin activation and Mitophagy in vitro and in vivo, followed by mitochondrial loss and dysfunction of some mitochondria, whereas mimics-823 exerted the opposite effects in CRC cells. The inhibition of Mitophagy by siParkin alleviated Ant-823-induced mitochondrial loss and dysfunction, as well as Apoptosis to a certain extent. Furthermore, piR-823 was found to interact with PINK1 and promote its ubiquitination and proteasome-dependent degradation, thus alleviating Mitophagy. Finally, these findings were verifed in samples obtained by patients affected by colorectal Cancer. In conclusion, we identify a novel mechanism by which piR-823 regulates Mitophagy during CRC tumorigenesis by increasing PINK1 degradation.

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