Mitochondrial retrograde signaling in gastric cancer: mtDNA mutations, ROS-driven NF-κB/HIF-1α activation, and Warburg effect amplification.

Mitochondrial retrograde signaling serves as a critical communication axis that links mitochondrial dysfunction to nuclear gene expression, shaping key pathways in gastric carcinogenesis. Gastric tumors frequently exhibit somatic mtDNA mutations, impaired oxidative phosphorylation, and elevated reactive oxygen species (ROS), collectively driving transcriptional reprogramming through activation of NF-κB and stabilization of HIF-1α. These retrograde signals promote inflammation, metabolic reprogramming, and resistance to apoptosis, ultimately reinforcing the Warburg phenotype characterized by enhanced aerobic glycolysis and lactate production. This review synthesizes current evidence on how mtDNA mutations, ROS-dependent transcription factor activation, and mitochondrial-nuclear metabolic crosstalk converge to promote malignant transformation. By integrating insights from mitochondrial biology, cancer genetics, and metabolic regulation, we outline a mechanistic framework that highlights mitochondrial retrograde signaling as a promising therapeutic target in gastric cancer.