Mitigation of depleted uranium-induced mitochondrial damage by ethylmalonic encephalopathy 1 protein via modulation of hydrogen sulfide and glutathione pathways.

Abstract

Depleted uranium (DU) is a byproduct of uranium enrichment, which can cause heavy-metal toxicity and radiation toxicity as well as serious damage to the kidneys. However, the mechanism of renal injury induced by DU is still unclear. This study aimed to explore the role of ethylmalonic encephalopathy 1 (ETHE1) in DU-induced mitochondrial dysfunction and elucidate the underlying mechanisms. Using ETHE1 gene knockout C57BL/6 mice (10 mg/kg DU) and renal cell models (500 µM DU) exposed to DU, we observed significantly reduced levels of hydrogen sulfide (H₂S) and glutathione (GSH), alongside decreased adenosine triphosphate (ATP) content and increased oxidative stress. Our results demonstrated that knocking out or silencing ETHE1 led to a significant reduction in H₂S and GSH levels, whereas the opposite occurred when was ETHE1 overexpressed. When the H₂S donor sodium hydrosulfide and GSH precursor N-acetylcysteine were used to treat animals or cells, cellular ATP levels were increased, oxidative stress markers were reduced, and kidney damage was mitigated. In addition, H₂S and GSH interacted with each other after DU poisoning. These findings suggest that the ETHE1/H₂S/GSH pathway plays a critical role in mediating DU-induced mitochondrial dysfunction in renal cells, highlighting potential therapeutic targets for mitigating the harmful effects of DU. Thus, this study expands our understanding of DU-induced renal damage pathways, providing avenues for further research and intervention strategies.