Glutamine Metabolism Promotes Renal Fibrosis through Regulation of Mitochondrial Energy Generation and Mitochondrial Fission

Cai, Yang; Tian, Beichen; Deng, Yuanjun; Liu, Lele; Zhang, Chunjiang; Peng, Wei; Li, Qian; Zhang, Tianjing; Han, Min; Xu, Gang

doi:10.7150/ijbs.89960

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Int J Biol Sci 2024; 20(3):987-1003. doi:10.7150/ijbs.89960 This issue Cite

Research Paper

Glutamine Metabolism Promotes Renal Fibrosis through Regulation of Mitochondrial Energy Generation and Mitochondrial Fission

Yang Cai^*, Beichen Tian^*, Yuanjun Deng, Lele Liu, Chunjiang Zhang, Wei Peng, Qian Li, Tianjing Zhang, Min Han^#✉, Gang Xu^#✉

Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan 430030, China.
* Yang Cai and Beichen Tian are co-first authors.
^# These authors contributed equally to this work.

Citation:

Cai Y, Tian B, Deng Y, Liu L, Zhang C, Peng W, Li Q, Zhang T, Han M, Xu G. Glutamine Metabolism Promotes Renal Fibrosis through Regulation of Mitochondrial Energy Generation and Mitochondrial Fission. Int J Biol Sci 2024; 20(3):987-1003. doi:10.7150/ijbs.89960. https://www.ijbs.com/v20p0987.htm

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Abstract

Fibroblast activation and proliferation is an essential phase in the progression of renal fibrosis. Despite the recognized significance of glutamine metabolism in cellular growth and proliferation, its precise pathophysiological relevance in renal fibrosis remains uncertain. Therefore, this study aims to investigate the involvement of glutamine metabolism in fibroblast activation and its possible mechanism. Our findings highlight the importance of glutamine metabolism in fibroblast activation and reveal that patients with severe fibrosis exhibit elevated serum glutamine levels and increased expression of kidney glutamine synthetase. Furthermore, the deprivation of glutamine metabolism in vitro and in vivo could inhibit fibroblast activation, thereby ameliorating renal fibrosis. It was also detected that glutamine metabolism is crucial for maintaining mitochondrial function and morphology. These effects may partially depend on the metabolic intermediate α-ketoglutaric acid. Moreover, glutamine deprivation led to upregulated mitochondrial fission in fibroblasts and the activation of the mammalian target of rapamycin / mitochondrial fission process 1 / dynamin-related protein 1 pathway. Thus, these results provide compelling evidence that the modulation of glutamine metabolism initiates the regulation of mitochondrial function, thereby facilitating the progression of renal fibrosis. Consequently, targeting glutamine metabolism emerges as a novel and promising avenue for therapeutic intervention and prevention of renal fibrosis.

Keywords: Renal fibrosis, Glutamine, Fibroblasts, Mitochondria, α-ketoglutaric acid, Mitochondrial fission

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APA

Cai, Y., Tian, B., Deng, Y., Liu, L., Zhang, C., Peng, W., Li, Q., Zhang, T., Han, M., Xu, G. (2024). Glutamine Metabolism Promotes Renal Fibrosis through Regulation of Mitochondrial Energy Generation and Mitochondrial Fission. International Journal of Biological Sciences, 20(3), 987-1003. https://doi.org/10.7150/ijbs.89960.

ACS

Cai, Y.; Tian, B.; Deng, Y.; Liu, L.; Zhang, C.; Peng, W.; Li, Q.; Zhang, T.; Han, M.; Xu, G. Glutamine Metabolism Promotes Renal Fibrosis through Regulation of Mitochondrial Energy Generation and Mitochondrial Fission. Int. J. Biol. Sci. 2024, 20 (3), 987-1003. DOI: 10.7150/ijbs.89960.

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CSE

Cai Y, Tian B, Deng Y, Liu L, Zhang C, Peng W, Li Q, Zhang T, Han M, Xu G. 2024. Glutamine Metabolism Promotes Renal Fibrosis through Regulation of Mitochondrial Energy Generation and Mitochondrial Fission. Int J Biol Sci. 20(3):987-1003.

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