Pharmaceutical formulations derived from Aristolochiaceae herbs, which contain aristolochic acids(AAs), are widely used for medicinal purposes. However, exposure to these plants and isolated AAs is linked to renal tox...Pharmaceutical formulations derived from Aristolochiaceae herbs, which contain aristolochic acids(AAs), are widely used for medicinal purposes. However, exposure to these plants and isolated AAs is linked to renal toxicity, known as AA nephropathy(AAN). Currently, the mechanisms underlying AAN are not fully understood, leading to unsatisfactory treatment strategies. In this study, we explored the protective role of 84-B10(5-[[2-(4-methoxyphenoxy)-5-(trifluoromethyl) phenyl] amino]-5-oxo-3-phenylpentanoic acid) against AAN. RNA-seq analysis revealed that the mitochondrion and peroxisome were the most affected cellular components following 84-B10 treatment in AAN mice. Consistently, 84-B10 treatment preserved mitochondrial ultrastructure, restored mitochondrial respiration, enhanced the expression of key transporters(carnitine palmitoyltransferase 2) and enzymes(acylCoenzyme A dehydrogenase, medium chain) involved in mitochondrial fatty acid β-oxidation, and reduced mitochondrial ROS generation in both aristolochic acid I(AAI)-challenged mice kidneys and cultured proximal tubular epithelial cells. Additionally, 84-B10 treatment increased the expression of key transporters(ATP binding cassette subfamily D) and rate-limiting enzymes(acyl-CoA oxidase 1) involved in peroxisomal fatty acid β-oxidation and restored peroxisomal redox balance. Knocking down LONP1 expression diminished the protective effects of 84-B10 against AAN, suggesting LONP1-dependent protection. In conclusion, our study provides evidence that AAN is associated with significant disturbances in both mitochondrial and peroxisomal functions. The LONP1 activator 84-B10 demonstrates therapeutic potential against AAN, likely by maintaining homeostasis in both mitochondria and peroxisomes.展开更多
基金supported by the National Key Research and Development Program of China (Nos. 2019YFA0802-702-1, 2022YFC2705100, 2022YFC2705105)the National Natural Science Foundation of China (Nos. 82070701, 82090022, and 8183-0020)+4 种基金the Natural Science Foundation of Jiangsu Province (No. BK20231130)the Social Development Foundation of Jiangsu Province(No. BE2021607)the “333” Talent Plan of Jiangsu Province (No.333-2022001)the Medical Research Project from Jiangsu Health and Health Commission (No. Z2022071)the Outstanding Youth Project from Nanjing Health and Health Commission (No.JQX22010)。
文摘Pharmaceutical formulations derived from Aristolochiaceae herbs, which contain aristolochic acids(AAs), are widely used for medicinal purposes. However, exposure to these plants and isolated AAs is linked to renal toxicity, known as AA nephropathy(AAN). Currently, the mechanisms underlying AAN are not fully understood, leading to unsatisfactory treatment strategies. In this study, we explored the protective role of 84-B10(5-[[2-(4-methoxyphenoxy)-5-(trifluoromethyl) phenyl] amino]-5-oxo-3-phenylpentanoic acid) against AAN. RNA-seq analysis revealed that the mitochondrion and peroxisome were the most affected cellular components following 84-B10 treatment in AAN mice. Consistently, 84-B10 treatment preserved mitochondrial ultrastructure, restored mitochondrial respiration, enhanced the expression of key transporters(carnitine palmitoyltransferase 2) and enzymes(acylCoenzyme A dehydrogenase, medium chain) involved in mitochondrial fatty acid β-oxidation, and reduced mitochondrial ROS generation in both aristolochic acid I(AAI)-challenged mice kidneys and cultured proximal tubular epithelial cells. Additionally, 84-B10 treatment increased the expression of key transporters(ATP binding cassette subfamily D) and rate-limiting enzymes(acyl-CoA oxidase 1) involved in peroxisomal fatty acid β-oxidation and restored peroxisomal redox balance. Knocking down LONP1 expression diminished the protective effects of 84-B10 against AAN, suggesting LONP1-dependent protection. In conclusion, our study provides evidence that AAN is associated with significant disturbances in both mitochondrial and peroxisomal functions. The LONP1 activator 84-B10 demonstrates therapeutic potential against AAN, likely by maintaining homeostasis in both mitochondria and peroxisomes.
