Mitochondrial Dysfunction in Ifosfamide-Induced Nephrotoxicity: Mechanisms and Possible Interventions

Ifosfamide is a chemotherapeutic agent used to treat aggressive solid tumors, but nephrotoxicity is a serious adverse effect and a risk factor for chronic kidney disease. Isophosphoramide mustard is the therapeutically active metabolite, whereas chloroacetaldehyde (CAA) is considered the nephrotoxic metabolite. The kidney injury predominantly affects the proximal tubule and has been linked to mitochondrial defects, although the cellular mechanisms remain incompletely understood. Here, we review the evidence for mitochondrial involvement and discuss potential therapeutic interventions. CAA is thought to disrupt oxidative phosphorylation, leading to ATP depletion and increased reactive oxygen species formation, which ultimately contributes to mitochondrial dysfunction. Additionally, CAA has been shown to interact with essential thiols such as glutathione and coenzyme A, and has been reported to impair lipid, protein metabolism and glucose synthesis. Collectively, these processes might contribute to tubulointerstitial nephritis, cellular senescence, and necrosis. Preclinical therapeutic interventions to prevent ifosfamide-induced nephrotoxicity have focused on protecting mitochondrial function and mitigating oxidative stress. These data indicate that antioxidants and glutathione precursors may reduce toxicity markers and preserve kidney histological structure. Ifosfamide-induced nephrotoxicity remains a clinical challenge as its mitochondrial mechanisms are not fully understood. To address this, we recommend investigating genetic susceptibility, and determining mitochondrial pathways, such as disrupted mitochondrial dynamics, mitochondrial DNA damage, and dysregulated energy signaling, through integrated molecular, functional, and metabolomic analyses in human-derived in vitro models. Additionally, we recommend evaluating nephroprotective strategies, including antioxidants, mitochondrial transplantation, and therapies that stimulate mitochondrial biogenesis, to identify interventions that prevent kidney injury while preserving antitumor efficacy.