Uranium inhibits mammalian mitochondrial cytochrome c oxidase and ATP synthase

As an emerging pollutant, uranium poses serious concerns to ecological and human health. The kidney has been established as a major deposition site and the most sensitive target organ for uranium poisoning, and the underlying toxicological mechanisms have been associated with oxidative stress and mitochondrial respiration. However, the identities of key molecular targets in uranium-induced toxicity remain elusive. In this study, we comprehensively evaluated the in vitro effects of uranium on ten critical enzymes in the mitochondrial respiration pathway and discovered that respiratory chain complex IV (cytochrome c oxidase) and complex V (ATP synthase) were strongly inhibited. The inhibitory effects were validated with mitochondria from human renal proximal tubule cells-the most affected renal site in uranium poisoning. The IC₅₀ values (around 1 mg/L) are physiologically relevant, as they are comparable to known kidney accumulation levels in uranium poisoning. In addition, these inhibitory effects could explain the well-documented uranium-induced reactive oxygen species generation and mitochondrial alterations. In conclusion, cytochrome c oxidase and ATP synthase are possibly key molecular targets underlying the toxic effects of uranium.