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Mitochondrial calcium uniporter promotes kidney aging in mice through inducing mitochondrial calcium-mediated renal tubular cell senescence

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Abstract

Renal tubular epithelial cell senescence plays a critical role in promoting and accelerating kidney aging and age-related renal fibrosis. Senescent cells not only lose their self-repair ability, but also can transform into senescence-associated secretory phenotype (SASP) to trigger inflammation and fibrogenesis. Recent studies show that mitochondrial dysfunction is critical for renal tubular cell senescence and kidney aging, and calcium overload and abnormal calcium-dependent kinase activities are involved in mitochondrial dysfunction-associated senescence. In this study we investigated the role of mitochondrial calcium overload and mitochondrial calcium uniporter (MCU) in kidney aging. By comparing the kidney of 2- and 24-month-old mice, we found calcium overload in renal tubular cells of aged kidney, accompanied by significantly elevated expression of MCU. In human proximal renal tubular cell line HK-2, pretreatment with MCU agonist spermine (10 μM) significantly increased mitochondrial calcium accumulation, and induced the production of reactive oxygen species (ROS), leading to renal tubular cell senescence and age-related kidney fibrosis. On the contrary, pretreatment with MCU antagonist RU360 (10 μM) or calcium chelator BAPTA-AM (10 μM) diminished D-gal-induced ROS generation, restored mitochondrial homeostasis, retarded cell senescence, and protected against kidney aging in HK-2 cells. In a D-gal-induced accelerated aging mice model, administration of BAPTA (100 μg/kg. i.p.) every other day for 8 weeks significantly alleviated renal tubuarl cell senescence and fibrosis. We conclude that MCU plays a key role in promoting renal tubular cell senescence and kidney aging. Targeting inhibition on MCU provides a new insight into the therapeutic strategy against kidney aging.

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Fig. 1: Calcium channel is induced in aged kidney and accompanied by dysfunction of calcium regulated activity.
Fig. 2: MCU is induced in aged kidney and accompanied by dysfunction of mitochondria.
Fig. 3: Activation of MCU promotes mitochondrial dysfunction and cellular senescence in cultured renal tubular epithelial cells.
Fig. 4: Inhibition of MCU promotes mitochondrial homeostasis in vitro.
Fig. 5: Inhibition of MCU alleviates cellular senescence in vitro.
Fig. 6: Chelation of calcium preserves mitochondrial function in vitro.
Fig. 7: Chelation of calcium inhibits cellular senescence in vitro.
Fig. 8: Chelation of calcium reduces mitochondrial dysfunction in kidneys in accelerated aging mice.
Fig. 9: Chelation of calcium alleviates renal tubular cell senescence and fibrosis in accelerated aging mice.
Fig. 10: The schematic presentation depicts the potential mechanism that MCU promotes mitochondrial dysfunction and cellular senescence.

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Data availability

Transcriptomic data presented in this study can be found at NCBI GEO database (GSE262514).

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Acknowledgements

This work was supported by National Natural Science Foundation of China (82225010, 82070707); and Guangdong Provincial Clinical Research Center for Kidney Disease (2020B1111170013).

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Authors and Affiliations

  1. State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Nephrology / Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Ya-bing **ong, Wen-yan Huang, **an Ling, Shan Zhou, **ao-xu Wang, **ao-long Li & Li-li Zhou

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Contributions

LLZ conceived the research and designed the experiments. YBX, WYH, XL, SZ, XXW, XLL and LLZ performed the experiments and contributed to acquisition and analysis of data. YBX created the figures and prepared the materials of this study. YBX and LLZ wrote the manuscript. All authors contributed to the article and approved the final manuscript.

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Correspondence to Li-li Zhou.

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**ong, Yb., Huang, Wy., Ling, X. et al. Mitochondrial calcium uniporter promotes kidney aging in mice through inducing mitochondrial calcium-mediated renal tubular cell senescence. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01298-5

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