Update publication information. As a well-known anti-diabetic drug, metformin has been repurposed for cancer treatment, but drug resistance and tumor metastasis observed recently have challenged its further application. Here, we found that long-term metformin exposure led to metabolic adaptation of HCC cells, which was characterized by obvious epithelial-mesenchymal transition (EMT) phenotype and compensatory elevated oxidative phosphorylation (OXPHOS). TOMM34, a translocase of the outer mitochondrial membrane, was identified to confer energetic flexibility thus promoting tumor metastasis in response to metformin-induced metabolic stress. Mechanistically, TOMM34 interacted and stabilized ATP5B to preserve F1F0-ATPase activity, which promoted mitochondrial OXPHOS and increased cellular ATP levels. This metabolic preference to OXPHOS suggested a large demand of energy supply of cancer cells to survival and spread under therapeutic stress.