Mfn2-related mitochondrial dysfunction regulates renal fibrosis through ferroptosis in chronic kidney disease.

Authors

Mingyu Zhang, Jingyu Wang, Ying Yang, Yutong Ma, Jiayi Huang, Hao Geng, Xiao Bai, Weihao Shang, Li Sun

Published in

Biochimica et biophysica acta. Molecular basis of disease. Pages 168432. Aug 24, 2026. Epub Aug 24, 2026.

Abstract

Chronic kidney disease (CKD) has become a global public health concern and renal fibrosis is the ultimate outcome of CKD progressing to end-stage renal disease. The effective treatment for renal fibrosis is limited. Ferroptosis is a type of programmed cell death characterized by iron deposition and lipid peroxidation. Mitochondria are essential organelles that play a critical role in maintaining cellular function. However, the effect of ferroptosis and mitochondrial dysfunction on renal fibrosis remains unclear. In this study, we confirmed that the expression of glutathione peroxidase 4 (GPX4) and Parkin was decreased in the renal tissues of CKD patients. Their levels were negatively correlated with serum creatinine (Scr) and C-reactive protein (CRP) and positively with estimated glomerular filtration rate (eGFR). Subsequently, we established unilateral ureteral obstruction (UUO) mice models and transforming growth factor-β1 (TGF-β1)-induced fibrosis-like changes in human renal tubular epithelial cells (HK-2 cells). The results showed that mitophagy-related proteins were decreased in renal fibrosis. Carbonylcyanide-3-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler, alleviates renal fibrosis by inhibiting ferroptosis, whereas mitochondrial division inhibitor 1 (Mdivi-1) exerts the opposite effect. In addition, bioinformatics analysis showed mitofusin2 (Mfn2) was involved in mitophagy and ferroptosis. We then conducted function experiments and revealed that Mfn2 knockdown inhibited mitophagy, exacerbated ferroptosis and renal fibrosis, while overexpression of Mfn2 promoted mitophagy, alleviated ferroptosis and renal fibrosis. In conclusion, this study is the first to illustrate the role and relationship of mitochondrial dysfunction, especially mitophagy, and ferroptosis in renal fibrosis and their interaction with Mfn2, providing new insights and potential therapeutic targets for renal fibrosis.

PMID:
42637154
Bibliographic data and abstract were imported from PubMed on 25 Aug 2026.

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