Activation of LONP1 by 84-B10 alleviates aristolochic acid nephropathy via re-establishing mitochondrial and peroxisomal homeostasis

Pharmaceutics formulations prepared from Aristolochiaceae herbs, which contain aristolochic acids (AAs), are broadly utilized for medicinal purposes, but exposure to these plants and isolated AAs is associated with renal toxicity, known as aristolochic acid nephropathy (AAN). AAN is characterized by proximal tubule injury and immune cell infiltration, contributing significantly to the global burden of chronic kidney disease. Currently, the underlying mechanisms of AAN remain incompletely understood, and as a result, treatment strategies for AAN remain unsatisfactory. In the present study, we investigated and observed a protective role of a novel mitochondrial Lon protease (LONP1) activator, 84-B10, against AAN. Through RNA-seq analysis, the mitochondrion and peroxisome were shown as the most impacted cellular components following 84-B10 treatment in AAN mice. Consistent with this, 84-B10 treatment showed the ability to protect mitochondrial ultrastructure, restore mitochondrial respiration, enhance the expression of key transporter (carnitine palmitoyltransferase 2) and enzyme (acyl-Coenzyme A dehydrogenase, medium chain) of mitochondrial fatty acid β-oxidation, and blunt mitochondrial ROS generation in both AAI-challenged mice kidneys and cultured proximal tubular epithelial cells. Additionally, 84-B10 treatment also increased the expression of key transporter (ATP binding cassette subfamily D) and rate-limiting enzyme (acyl-CoA oxidase 1) involved in peroxisomal fatty acid β-oxidation and restored peroxisomal redox balance both in vivo and in vitro. Finally, we identified that knocking down LONP1 expression blunted the protective effect of 84-B10 against AAN, suggesting a LONP1-dependent protection. In conclusion, our study provides the evidence that AAN is accompanied by pronounced disturbances in both mitochondrial and peroxisomal function, and the LONP1 activator 84-B10 exhibits therapeutic potential against AAN, possibly by maintaining homeostasis in both mitochondrion and peroxisomes.