Tang Mingzhu, Rong Dade, Gao Xiangzheng, Lu Guang, Tang Haimei, Wang Peng, Shao Ning-Yi, Xia Dajing, Feng Xin-Hua, He Wei-Feng, Chen Weilin, Lu Jia-Hong, Liu Wei, Shen Han-Ming
Faculty of Healthy Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China.
Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
Cell Discov. 2025 Mar 11;11(1):22. doi: 10.1038/s41421-025-00774-4.
PTEN-induced kinase-1 (PINK1) is a crucial player in selective clearance of damaged mitochondria via the autophagy-lysosome pathway, a process termed mitophagy. Previous studies on PINK1 mainly focused on its post-translational modifications, while the transcriptional regulation of PINK1 is much less understood. Herein, we reported a novel mechanism in control of PINK1 transcription by SMAD Family Member 3 (SMAD3), an essential component of the transforming growth factor beta (TGFβ)-SMAD signaling pathway. First, we observed that mitochondrial depolarization promotes PINK1 transcription, and SMAD3 is likely to be the nuclear transcription factor mediating PINK1 transcription. Intriguingly, SMAD3 positively transactivates PINK1 transcription independent of the canonical TGFβ signaling components, such as TGFβ-R1, SMAD2 or SMAD4. Second, we found that mitochondrial depolarization activates SMAD3 via PINK1-mediated phosphorylation of SMAD3 at serine 423/425. Therefore, PINK1 and SMAD3 constitute a positive feedforward loop in control of mitophagy. Finally, activation of PINK1 transcription by SMAD3 provides an important pro-survival signal, as depletion of SMAD3 sensitizes cells to cell death caused by mitochondrial stress. In summary, our findings identify a non-canonical function of SMAD3 as a nuclear transcriptional factor in regulation of PINK1 transcription and mitophagy and a positive feedback loop via PINK1-mediated SMAD3 phosphorylation and activation. Understanding this novel regulatory mechanism provides a deeper insight into the pathological function of PINK1 in the pathogenesis of neurodegenerative diseases such as Parkinson's disease.
PTEN诱导激酶1（PINK1）是通过自噬-溶酶体途径选择性清除受损线粒体（即线粒体自噬过程）中的关键因子。先前对PINK1的研究主要集中在其翻译后修饰，而对PINK1的转录调控了解较少。在此，我们报道了一种由SMAD家族成员3（SMAD3）调控PINK1转录的新机制，SMAD3是转化生长因子β（TGFβ）-SMAD信号通路的重要组成部分。首先，我们观察到线粒体去极化促进PINK1转录，且SMAD3可能是介导PINK1转录的核转录因子。有趣的是，SMAD3独立于经典的TGFβ信号成分（如TGFβ-R1、SMAD2或SMAD4）正向反式激活PINK1转录。其次，我们发现线粒体去极化通过PINK1介导的SMAD3丝氨酸423/425位点磷酸化激活SMAD3。因此，PINK1和SMAD3在调控线粒体自噬中构成一个正向前馈环。最后，SMAD3对PINK1转录的激活提供了一个重要的促生存信号，因为SMAD3的缺失使细胞对线粒体应激引起的细胞死亡敏感。总之，我们的研究结果确定了SMAD3作为核转录因子在调控PINK1转录和线粒体自噬中的非经典功能，以及通过PINK1介导的SMAD3磷酸化和激活形成的正反馈环。了解这一新的调控机制有助于更深入地了解PINK1在帕金森病等神经退行性疾病发病机制中的病理功能。
