PPA1 promotes oxidative phosphorylation and malignant progression of colorectal cancer under glucose restriction via AMPK/ULK1/FUNDC1-mediated mitophagy

Metabolic reprogramming is a hallmark of colorectal cancer (CRC). Pyrophosphatase 1(PPA1), an energy-metabolizing enzyme, has been observed to be upregulated in multiple cancers and implicated in tumorigenesis and progression. However, its specific role in metabolic rewiring of CRC and the underlying molecular mechanisms remain poorly understood. Our study revealed that PPA1 is highly expressed in CRC epithelial cells and is significantly associated with advanced tumor size, lymph node status, TNM stage, and reduced overall survival in patients. Knockdown of PPA1 suppressed CRC tumorigenesis and metastasis both in vitro and in vivo. Under glucose-restricted conditions, PPA1 depletion impaired OXPHOS in CRC cells, leading to reduced oxygen consumption, decreased ATP production, elevated mitochondrial ROS levels, and decline in mitochondrial membrane potential. Mechanistically, PPA1 promotes phosphorylation of AMPK at Thr172, thereby facilitating phosphorylation of ULK1 at Ser467 and Ser555, and subsequently enhancing FUNDC1 phosphorylation at Ser17. This phosphorylation cascade initiates mitophagy to sustain OXPHOS metabolic activity, thereby driving CRC malignant progression. In summary, PPA1 sustains OXPHOS and drives malignant progression in CRC under glucose restriction by promoting AMPK/ULK1/FUNDC1-mediated mitophagy.