线粒体自噬（Mitophagy）通过选择性通过自噬消除功能异常和过剩的线粒体，在诸如低氧等压力条件下对细胞稳态至关重要。Mitophagy的失调越来越与多种疾病相关，包括神经退行性疾病和癌症。三阴性乳腺癌（TNBC）是一种非常具有攻击性的乳腺癌亚型，报道称其具有低氧特征。然而，低氧的TNBC中Mitophagy的作用以及潜在的分子机制还不为人所知。在这里，我们确定了胆碱代谢中的关键酶GPCPD1（甘油磷酸胆碱磷酸酯酶1）作为低氧诱导的Mitophagy的必需介质。在低氧条件下，我们发现GPCPD1被LYPLA1去鞘脂化，从而促进GPCPD1重定位到外线粒体膜（OMM）。线粒体定位的GPCPD1可以与VDAC1结合，VDAC1是PRKN / PARKIN依赖的泛素化的底物，从而干扰VDAC1的寡聚化。VDAC1单体的增加提供了更多的锚点位点来吸附PRKN介导的多泛素化，从而引发Mitophagy。此外，我们发现GPCPD1介导的Mitophagy在体内外对TNBC的肿瘤生长和转移具有促进作用。我们进一步确定GPCPD1可作为TNBC的独立预后指标。总之，我们的研究为了解低氧诱导的Mitophagy提供了重要见解，并阐明了GPCPD1可能作为未来开发TNBC患者新型治疗的潜在靶标。

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.