Hypoxia-induced GPCPD1 depalmitoylation triggers mitophagy via regulating PRKN-mediated ubiquitination of VDAC1
Hypoxia-induced GPCPD1 depalmitoylation triggers mitophagy via regulating PRKN-mediated ubiquitination of VDAC1
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DOI：
10.1080/15548627.2023.2182482
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发表时间：
2023-03-03
期刊：
影响因子：
13.3
通讯作者：
Yang, Qifeng
中科院分区：
文献类型：
--
作者：
Liu, Ying;Zhang, Hanwen;Yang, Qifeng
线粒体自噬通过自噬选择性地消除功能失调和过量的线粒体，对于缺氧等应激下的细胞内稳态至关重要。线粒体自噬的失调越来越多地与包括神经退行性疾病和癌症在内的许多疾病联系在一起。据报道，三阴性乳腺癌（TNBC）是一种高度侵袭性的乳腺癌亚型，其特征在于缺氧。然而，线粒体自噬在缺氧TNBC中的作用以及潜在的分子机制在很大程度上未被探索。在这里，我们确定了GPCPD 1（甘油磷酸胆碱磷酸二酯酶1），胆碱代谢的关键酶，作为一个重要的介质在缺氧诱导的线粒体自噬。在缺氧条件下，我们发现GPCPD 1被LYPLA 1脱棕榈酰化，这有助于GPCPD 1重新定位到线粒体外膜（OMM）。线粒体定位的GPCPD 1可以结合VDAC 1，PRKN/PARKIN依赖性泛素化的底物，从而干扰VDAC 1的寡聚化。VDAC 1单体的增加提供了更多的锚位点来募集PRKN介导的多聚泛素化，从而引发线粒体自噬。此外，我们发现GPCPD 1介导的线粒体自噬在体外和体内都对TNBC的肿瘤生长和转移具有促进作用。我们进一步确定GPCPD 1可以作为TNBC的独立预后指标。总之，我们的研究为缺氧诱导的线粒体自噬机制的理解提供了重要的见解，并阐明了GPCPD 1可以作为未来开发TNBC患者新疗法的潜在靶点。
Mitophagy, which selectively eliminates the dysfunctional and excess mitochondria by autophagy, is crucial for cellular homeostasis under stresses such as hypoxia. Dysregulation of mitophagy has been increasingly linked to many disorders including neurodegenerative disease and cancer. Triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype, is reported to be characterized by hypoxia. However, the role of mitophagy in hypoxic TNBC as well as the underlying molecular mechanism is largely unexplored. Here, we identified GPCPD1 (glycerophosphocholine phosphodiesterase 1), a key enzyme in choline metabolism, as an essential mediator in hypoxia-induced mitophagy. Under the hypoxic condition, we found that GPCPD1 was depalmitoylated by LYPLA1, which facilitated the relocating of GPCPD1 to the outer mitochondrial membrane (OMM). Mitochondria-localized GPCPD1 could bind to VDAC1, the substrate for PRKN/PARKIN-dependent ubiquitination, thus interfering with the oligomerization of VDAC1. The increased monomer of VDAC1 provided more anchor sites to recruit PRKN-mediated polyubiquitination, which consequently triggered mitophagy. In addition, we found that GPCPD1-mediated mitophagy exerted a promotive effect on tumor growth and metastasis in TNBC both in vitro and in vivo. We further determined that GPCPD1 could serve as an independent prognostic indicator in TNBC. In conclusion, our study provides important insights into a mechanistic understanding of hypoxia-induced mitophagy and elucidates that GPCPD1 could act as a potential target for the future development of novel therapy for TNBC patients.