Prkn, also known as parkin RBR E3 ubiquitin protein ligase, is crucial for protein ubiquitination and mitophagy, a process of selectively eliminating damaged mitochondria. It functions within the PINK1-Prkn pathway, which is central to mitochondrial quality control. Genetic models, such as gene knockout mouse models, have been instrumental in studying Prkn's functions [1,3,4,5,6,7,8,9].

In a study on COPD pathogenesis, prkn knockout (KO) mice showed enhanced airway wall thickening with emphysematous changes after cigarette smoke exposure, along with damaged mitochondria accumulation, increased oxidative modifications, and accelerated cellular senescence in airway epithelial cells. In vitro, Prkn overexpression could induce mitophagy even with reduced PINK1 levels, while PINK1 overexpression couldn't recover impaired mitophagy from Prkn knockdown, suggesting Prkn is rate-limiting in PINK1-Prkn-mediated mitophagy during cigarette smoke extract exposure [1]. In triple-negative breast cancer, hypoxia-induced GPCPD1 depalmitoylation regulated Prkn-mediated ubiquitination of VDAC1 to trigger mitophagy, promoting tumor growth and metastasis [2]. In colorectal cancer, USP26 interacted with Prkn, facilitating its deubiquitination at K129, reducing its activity and restraining Prkn-mediated mitophagy to drive tumorigenesis [7]. In breast cancer, MANF mediated mitophagy by binding to Prkn in mitochondria under glucose-starvation conditions, promoting cell survival [9].

In summary, Prkn is essential for mitophagy and mitochondrial quality control. Model-based research, especially using Prkn KO mouse models, has revealed its significance in diseases like COPD, triple-negative breast cancer, colorectal cancer, and breast cancer. Understanding Prkn's functions provides insights into disease mechanisms and potential therapeutic targets for these conditions.

References:

1. Araya, Jun, Tsubouchi, Kazuya, Sato, Nahoko, Nakayama, Katsutoshi, Kuwano, Kazuyoshi. 2018. PRKN-regulated mitophagy and cellular senescence during COPD pathogenesis. In Autophagy, 15, 510-526. doi:10.1080/15548627.2018.1532259. https://pubmed.ncbi.nlm.nih.gov/30290714/

2. Liu, Ying, Zhang, Hanwen, Liu, Yiwei, Zhang, Ning, Yang, Qifeng. 2023. Hypoxia-induced GPCPD1 depalmitoylation triggers mitophagy via regulating PRKN-mediated ubiquitination of VDAC1. In Autophagy, 19, 2443-2463. doi:10.1080/15548627.2023.2182482. https://pubmed.ncbi.nlm.nih.gov/36803235/

3. Clausen, Lene, Okarmus, Justyna, Voutsinos, Vasileios, Lindorff-Larsen, Kresten, Hartmann-Petersen, Rasmus. 2024. PRKN-linked familial Parkinson's disease: cellular and molecular mechanisms of disease-linked variants. In Cellular and molecular life sciences : CMLS, 81, 223. doi:10.1007/s00018-024-05262-8. https://pubmed.ncbi.nlm.nih.gov/38767677/

4. Yan, Chaojun, Gong, Longlong, Chen, Li, Désaubry, Laurent, Song, Zhiyin. 2019. PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. In Autophagy, 16, 419-434. doi:10.1080/15548627.2019.1628520. https://pubmed.ncbi.nlm.nih.gov/31177901/

5. Niu, Kaifeng, Fang, Hongbo, Chen, Zixiang, Balajee, Adayabalam S, Zhao, Yongliang. 2019. USP33 deubiquitinates PRKN/parkin and antagonizes its role in mitophagy. In Autophagy, 16, 724-734. doi:10.1080/15548627.2019.1656957. https://pubmed.ncbi.nlm.nih.gov/31432739/

6. Yamada, Tatsuya, Dawson, Ted M, Yanagawa, Toru, Iijima, Miho, Sesaki, Hiromi. 2019. SQSTM1/p62 promotes mitochondrial ubiquitination independently of PINK1 and PRKN/parkin in mitophagy. In Autophagy, 15, 2012-2018. doi:10.1080/15548627.2019.1643185. https://pubmed.ncbi.nlm.nih.gov/31339428/

7. Wu, Qi, Wang, Zhihong, Chen, Siqi, Wang, Guihua, Hu, Junbo. 2024. USP26 promotes colorectal cancer tumorigenesis by restraining PRKN-mediated mitophagy. In Oncogene, 43, 1581-1593. doi:10.1038/s41388-024-03009-0. https://pubmed.ncbi.nlm.nih.gov/38565942/

8. Xian, Hongxu, Liou, Yih-Cherng. 2019. Loss of MIEF1/MiD51 confers susceptibility to BAX-mediated cell death and PINK1-PRKN-dependent mitophagy. In Autophagy, 15, 2107-2125. doi:10.1080/15548627.2019.1596494. https://pubmed.ncbi.nlm.nih.gov/30894073/

9. Xiong, Zhenchong, Yang, Lin, Zhang, Chao, Song, Libing, Wang, Xi. 2024. MANF facilitates breast cancer cell survival under glucose-starvation conditions via PRKN-mediated mitophagy regulation. In Autophagy, 21, 80-101. doi:10.1080/15548627.2024.2392415. https://pubmed.ncbi.nlm.nih.gov/39147386/