Pink1-KO Mouse

PINK1, also known as PTEN-induced kinase 1, is a serine/threonine-protein kinase crucial for mitochondrial quality control. It plays a key role in the PINK1/Parkin-mediated ubiquitin-dependent mitophagy pathway, which is essential for maintaining mitochondrial health, homeostasis, and eliminating defective mitochondria via lysosomal degradation [1,2,3,4,5]. This pathway is of great significance in energy-intensive neuronal cells, and its dysfunction is associated with neurodegenerative diseases, especially Parkinson's disease [1,2,3,5].

In Parkinson's disease models, loss-of-function mutations in PINK1 and Parkin lead to mitochondrial dysfunction and parkinsonism in humans, and similar phenotypes in model organisms [8]. PINK1 accumulates on the outer membrane of damaged mitochondria, activates Parkin's E3 ubiquitin ligase activity, and recruits Parkin to the dysfunctional mitochondrion. Then, Parkin ubiquitinates outer mitochondrial membrane proteins to trigger selective autophagy [3]. In cells with PARK7 mutations (encoding DJ-1), DJ-1 was found to be essential for PINK1/parkin-mediated mitophagy, as its loss blocked mitophagy downstream by inhibiting the recruitment of the selective autophagy receptor optineurin to depolarized mitochondria [6]. Also, PINK1 phosphorylates ubiquitin at serine 65, which activates Parkin E3 ubiquitin ligase activity [7].

In conclusion, PINK1 is a vital regulator in mitochondrial quality control, particularly in the mitophagy pathway. Studies on PINK1-deficient models, including those related to Parkinson's disease, have revealed its essential role in maintaining mitochondrial function and provided insights into the pathogenesis of neurodegenerative diseases. These findings may offer potential therapeutic strategies centered around the regulation of mitophagy [1,2,3,5].

References:

1. Li, Jie, Yang, Dongming, Li, Zhiping, Zhao, Deming, Yang, Lifeng. 2022. PINK1/Parkin-mediated mitophagy in neurodegenerative diseases. In Ageing research reviews, 84, 101817. doi:10.1016/j.arr.2022.101817. https://pubmed.ncbi.nlm.nih.gov/36503124/

2. Narendra, Derek P, Youle, Richard J. 2024. The role of PINK1-Parkin in mitochondrial quality control. In Nature cell biology, 26, 1639-1651. doi:10.1038/s41556-024-01513-9. https://pubmed.ncbi.nlm.nih.gov/39358449/

3. Pickrell, Alicia M, Youle, Richard J. . The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease. In Neuron, 85, 257-73. doi:10.1016/j.neuron.2014.12.007. https://pubmed.ncbi.nlm.nih.gov/25611507/

4. Eiyama, Akinori, Okamoto, Koji. 2015. PINK1/Parkin-mediated mitophagy in mammalian cells. In Current opinion in cell biology, 33, 95-101. doi:10.1016/j.ceb.2015.01.002. https://pubmed.ncbi.nlm.nih.gov/25697963/

5. Nguyen, Thanh N, Padman, Benjamin S, Lazarou, Michael. 2016. Deciphering the Molecular Signals of PINK1/Parkin Mitophagy. In Trends in cell biology, 26, 733-744. doi:10.1016/j.tcb.2016.05.008. https://pubmed.ncbi.nlm.nih.gov/27291334/

6. Imberechts, Dorien, Kinnart, Inge, Wauters, Fieke, Verfaillie, Catherine, Vandenberghe, Wim. . DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy. In Brain : a journal of neurology, 145, 4368-4384. doi:10.1093/brain/awac313. https://pubmed.ncbi.nlm.nih.gov/36039535/

7. Kane, Lesley A, Lazarou, Michael, Fogel, Adam I, Banerjee, Soojay, Youle, Richard J. 2014. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. In The Journal of cell biology, 205, 143-53. doi:10.1083/jcb.201402104. https://pubmed.ncbi.nlm.nih.gov/24751536/

8. Narendra, Derek P, Jin, Seok Min, Tanaka, Atsushi, Cookson, Mark R, Youle, Richard J. 2010. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. In PLoS biology, 8, e1000298. doi:10.1371/journal.pbio.1000298. https://pubmed.ncbi.nlm.nih.gov/20126261/