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Lin 2024 Apoptosis

From Bioblast
Publications in the MiPMap
Lin HY, Liang CJ, Yang MY, Chen PL, Wang TM, Chen YH, Shih YH, Liu W, Chiu CC, Chiang CK, Lin CS, Lin HC (2024) Critical roles of tubular mitochondrial ATP synthase dysfunction in maleic acid-induced acute kidney injury.

Β» Apoptosis [Epub ahead of print]. PMID: 38281282 Open Access

Lin Hugo Y-H, Liang Chan-Jung, Yang Ming-Yu, Chen Phang-Lang, Wang Tzu-Ming, Chen Yen-Hua, Shih Yao-Hsiang, Liu Wangta, Chiu Chien-Chih, Chiang Chih-Kang, Lin Chang-Shen, Lin Han-Chen (2024) Apoptosis

Abstract: Maleic acid (MA) induces renal tubular cell dysfunction directed to acute kidney injury (AKI). AKI is an increasing global health burden due to its association with mortality and morbidity. However, targeted therapy for AKI is lacking. Previously, we determined mitochondrial-associated proteins are MA-induced AKI affinity proteins. We hypothesized that mitochondrial dysfunction in tubular epithelial cells plays a critical role in AKI. In vivo and in vitro systems have been used to test this hypothesis. For the in vivo model, C57BL/6 mice were intraperitoneally injected with 400 mg/kg body weight MA. For the in vitro model, HK-2 human proximal tubular epithelial cells were treated with 2 mM or 5 mM MA for 24 h. AKI can be induced by administration of MA. In the mice injected with MA, the levels of blood urea nitrogen (BUN) and creatinine in the sera were significantly increased (p < 0.005). From the pathological analysis, MA-induced AKI aggravated renal tubular injuries, increased kidney injury molecule-1 (KIM-1) expression and caused renal tubular cell apoptosis. At the cellular level, mitochondrial dysfunction was found with increasing mitochondrial reactive oxygen species (ROS) (p < 0.001), uncoupled mitochondrial respiration with decreasing electron transfer system activity (p < 0.001), and decreasing ATP production (p < 0.05). Under transmission electron microscope (TEM) examination, the cristae formation of mitochondria was defective in MA-induced AKI. To unveil the potential target in mitochondria, gene expression analysis revealed a significantly lower level of ATPase6 (p < 0.001). Renal mitochondrial protein levels of ATP subunits 5A1 and 5C1 (p < 0.05) were significantly decreased, as confirmed by protein analysis. Our study demonstrated that dysfunction of mitochondria resulting from altered expression of ATP synthase in renal tubular cells is associated with MA-induced AKI. This finding provides a potential novel target to develop new strategies for better prevention and treatment of MA-induced AKI. β€’ Keywords: AKI, ATP synthase, Maleic acid, Mitochondria β€’ Bioblast editor: Plangger M

Labels: MiParea: Respiration 

Organism: Human  Tissue;cell: Kidney  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k