Phosphate-induced vascular calcification, characterized by induction of osteogenic programs, mineral vesicle release, and apoptosis, is prevalent in patients with kidney disease. Zhao et al. provide a mechanistic link between phosphate-induced calcification and increased mitochondrial membrane potential, increased mitochondrial reactive oxygen species, activation of the nuclear factor-κB pathway, and subsequent expression of osteogenic genes and vascular mineralization. This link clarifies the intracellular mechanism of vascular calcification and may allow exploration of antioxidants as therapeutic agents for vascular calcification.