###### Abstract  
Aristolochic acids, compounds derived from _Aristolochicae_ plant species, are associated with significant renal nephrotoxicity and carcinogenicity. Aristolochic acid I (AAI), the most predominant and potent of these compounds, is a primary etiological agent in acute and chronic kidney diseases such as Aristolochic Acid Nephropathy (AAN) and Balkan Endemic Nephropathy (BEN). Due to the kidneys' critical role in xenobiotic excretion, they are the primary organs affected by AAI toxicity. Recent in vitro and in vivo studies have highlighted mitochondrial dysfunction as a crucial factor in the pathogenesis of these kidney diseases. This review provides an update on the recent advances in understanding the causes of acquired mitochondrial dysfunction within the context of AAN and BEN. Key findings include the identification of mitochondrial DNA depletion, loss of mitochondrial membrane potential, and decreased ATP production as significant contributors to kidney damage. Additionally, oxidative stress markers and inflammatory mediators have been implicated in disease progression. Potential therapeutic approaches, such as the use of antioxidants like vitamin C and catalpol, have shown promise in mitigating AAI-induced cytotoxicity. Furthermore, future predictive approaches like pharmacogenomics could pave the way for novel mitochondria-targeted treatments. A comprehensive characterization of mitochondrial function, its underlying molecular mechanisms, and specific biomarkers could offer valuable insights and potential therapeutic options, significantly impacting the current management of AAN and BEN. mitochondria; renal disease; phytotoxins; oxidative stress; environmental markers +
Footnote †: journal: _Sciences_  
found in _Aristololiaaceae_ family plants, which is used in traditional medicine for several ailments affecting various organs [2; 3; 4]. There are two well-described environmentally induced kidney diseases, Balkan Endemic Nephropathy (BEN) and Aristolochic Acid Nephropathy (AAN) [5; 6]; although these kidney diseases were discovered 40 years apart, the common environmental factor causing them is AAI [7; 8]. For over 60 years, BEN, a slowly progressing loss of kidney function, has been affecting residents of rural villages in Romania, Bulgaria, Serbia, Croatia, and Bosnia-Herzegovina. Over 25,000 individuals have suffered from this disease, with variations in the age of onset from 40 to 70 years [9]. Many possible causing factors were suggested in BEN causation since its original description in the 1950s, and as early as 1969, research from Serbia suggested that the BEN outbreak in the Balkan Peninsula could be due to itatrogenic exposure to AAs through the food chain, proposing the ingestion of flour contaminated with _Aristololia_ seeds [10]. Further studies demonstrated that AAs could indeed contaminate crop plants through absorption from the soil and uptake by neighboring food crops through their roots, being deposited into the grains and other cultivated vegetables [11]. Despite intensive research to find other potential causative agents, AAs were shown to be one of the main culprits of this disease [12]. Evidence from BEN studies provides an example of toxic renal injury induced by phytotoxins found in the local environment. Those affected by BEN present tubular proteinuria, impaired renal concentrating capacity, reduced glomerular filtration rate (GFR), and interstitial fibrosis with tubular atrophy [13]. In the early 1990s, a new epidemic of rapidly progressive tubulointerstitial nephritis was reported in a cohort of young female patients in Belgium. This acute kidney disease was rapidly associated with the intake of slimming pills containing Chinese herbs, which incidentally contained AAs, and the disease was named AAN [14]. _Aristololia_ plant species have been used since ancient times in traditional Chinese medicine to treat a wide range of diseases and symptoms.