Uranium inhibits mammalian mitochondrial cytochrome c oxidase and ATP synthase.

Abstract

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.

• Authors: Libing Yu, Wenjing Li, Jian Chu, Chun Chen, Xijian Li, Wei Tang, Binyuan Xia, Zhonghua Xiong
• Journal: Environmental pollution (Barking, Essex : 1987) (Environ Pollut) Vol. 271 Pg. 116377 (Feb 15 2021) ISSN: 1873-6424 [Electronic] England
• PMID: 33401214 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Uranium
• Adenosine Triphosphate
• Electron Transport Complex IV

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Electron Transport Complex IV (metabolism)
• Humans
• Mitochondria (metabolism)
• Oxidative Stress
• Uranium (metabolism, toxicity)