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Mitochondrial pyruvate carrier 2 mitigates acute kidney injury via sustaining mitochondrial metabolism
1Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
Abstract:
Cisplatin, a chemotherapeutic drug, can result in acute kidney injury (AKI). Currently, there are no effective prevention methods. An incomplete understanding of the pathogenesis of AKI is a major barrier to the development of effective therapies. Metabolism reprogramming shift to glycolysis was involved in AKI pathogenesis. Glycolysis results in the pyruvate production. The mitochondrial pyruvate carrier (MPC) conveys cytosol pyruvate into mitochondria, promoting the tricarboxylic acid cycle. In this current study, we found a reduction in MPC2 expression in mice and cultured HK2 cells with cisplatin-induced AKI. MPC2 overexpression attenuated cisplatin-mediated nephrotoxicity both in vitro and in vivo via restoring pyruvate metabolism and mitochondrial function. Knockdown of MPC2 reversed this effect. Furthermore, artemether, an MPC2 potential activator, could mitigate AKI via regulating MPC2-mediated pyruvate metabolism. Our findings revealed that MPC2-pyruvate metabolism axis was a promising strategy to alleviate AKI induced by cisplatin.
Insights
This study identifies the mitochondrial pyruvate carrier 2 (MPC2) as a key factor in cisplatin-induced acute kidney injury (AKI). Enhancing MPC2 function may offer a novel therapeutic strategy to prevent kidney damage from chemotherapy.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Cisplatin chemotherapy can cause acute kidney injury (AKI), a serious side effect with no current preventative treatments.
- Understanding AKI pathogenesis is crucial for developing effective therapies, with metabolic reprogramming, particularly glycolysis, implicated in its development.
- The mitochondrial pyruvate carrier (MPC) is vital for pyruvate transport into mitochondria, supporting the tricarboxylic acid cycle.
Purpose of the Study:
- To investigate the role of the mitochondrial pyruvate carrier 2 (MPC2) in cisplatin-induced AKI.
- To explore MPC2 as a potential therapeutic target for mitigating cisplatin nephrotoxicity.
Main Methods:
- Examined MPC2 expression in mouse models and HK2 cells with cisplatin-induced AKI.
- Utilized MPC2 overexpression and knockdown techniques in vitro and in vivo.
- Assessed the impact of artemether, a potential MPC2 activator, on cisplatin-induced nephrotoxicity.
Main Results:
- MPC2 expression was reduced in cisplatin-induced AKI models.
- Overexpression of MPC2 protected against cisplatin-induced nephrotoxicity by restoring pyruvate metabolism and mitochondrial function.
- Knockdown of MPC2 exacerbated AKI, while artemether treatment mitigated AKI by modulating MPC2 activity.
Conclusions:
- The MPC2-pyruvate metabolism axis plays a critical role in cisplatin-induced AKI.
- Targeting MPC2-mediated pyruvate metabolism presents a promising therapeutic strategy for preventing chemotherapy-induced kidney damage.
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