Inhibition of KMO Ameliorates Myocardial Ischemia Injury via Maintaining Mitochondrial Fusion and Fission Balance

Lai, Qiong; Wu, Lingling; Dong, Shuhong; Zhu, Xiaozhou; Fan, Zhaoyang; Kou, Junping; Liu, Fuming; Yu, Boyang; Li, Fang

doi:10.7150/ijbs.83392

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Int J Biol Sci 2023; 19(10):3077-3098. doi:10.7150/ijbs.83392 This issue Cite

Research Paper

Inhibition of KMO Ameliorates Myocardial Ischemia Injury via Maintaining Mitochondrial Fusion and Fission Balance

Qiong Lai^1#, Lingling Wu^1#, Shuhong Dong¹, Xiaozhou Zhu¹, Zhaoyang Fan¹, Junping Kou¹, Fuming Liu^2✉, Boyang Yu^1✉, Fang Li^1✉

1. Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China.
2. Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
^#These authors contributed equally: Qiong Lai, Lingling Wu

✉ Corresponding authors: Fuming Liu, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China, E-mail: doctor.liufumingcom; Boyang Yu, Jiangsu Key Laboratory of TCM Evaluation and Translation Research, Re More

Citation:

Lai Q, Wu L, Dong S, Zhu X, Fan Z, Kou J, Liu F, Yu B, Li F. Inhibition of KMO Ameliorates Myocardial Ischemia Injury via Maintaining Mitochondrial Fusion and Fission Balance. Int J Biol Sci 2023; 19(10):3077-3098. doi:10.7150/ijbs.83392. https://www.ijbs.com/v19p3077.htm

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Abstract

Looking for early diagnostic markers and therapeutic targets is the key to ensuring prompt treatment of myocardial ischemia (MI). Here, a novel biomarker xanthurenic acid (XA) was identified based on metabolomics and exhibited high sensitivity and specificity in the diagnosis of MI patients. Additionally, the elevation of XA was proved to induce myocardial injury in vivo by promoting myocardial apoptosis and ferroptosis. Combining metabolomics and transcriptional data further revealed that kynurenine 3-monooxygenase (KMO) profoundly increased in MI mice, and was closely associated with the elevation of XA. More importantly, pharmacological or heart-specific inhibition of KMO obviously suppressed the elevation of XA and profoundly ameliorated the OGD-induced cardiomyocytes injury and the ligation-induced MI injury. Mechanistically, KMO inhibition effectively restrained myocardial apoptosis and ferroptosis by modulating mitochondrial fission and fusion. In addition, virtual screening and experimental validation were adopted to identify ginsenoside Rb3 as a novel inhibitor of KMO and exhibited great cardioprotective effects by regulating mitochondrial dynamical balance. Taken together, targeting KMO may provide a new approach for the clinical treatment of MI through maintaining mitochondrial fusion and fission balance, and ginsenoside Rb3 showed great potential to be developed as a novel therapeutic drug targeting KMO.

Keywords: Myocardial ischemia, Xanthurenic acid, Kynurenine 3-monooxygenase, Mitochondrial fusion and fission, Ginsenoside Rb3

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APA

Lai, Q., Wu, L., Dong, S., Zhu, X., Fan, Z., Kou, J., Liu, F., Yu, B., Li, F. (2023). Inhibition of KMO Ameliorates Myocardial Ischemia Injury via Maintaining Mitochondrial Fusion and Fission Balance. International Journal of Biological Sciences, 19(10), 3077-3098. https://doi.org/10.7150/ijbs.83392.

ACS

Lai, Q.; Wu, L.; Dong, S.; Zhu, X.; Fan, Z.; Kou, J.; Liu, F.; Yu, B.; Li, F. Inhibition of KMO Ameliorates Myocardial Ischemia Injury via Maintaining Mitochondrial Fusion and Fission Balance. Int. J. Biol. Sci. 2023, 19 (10), 3077-3098. DOI: 10.7150/ijbs.83392.

NLM

CSE

Lai Q, Wu L, Dong S, Zhu X, Fan Z, Kou J, Liu F, Yu B, Li F. 2023. Inhibition of KMO Ameliorates Myocardial Ischemia Injury via Maintaining Mitochondrial Fusion and Fission Balance. Int J Biol Sci. 19(10):3077-3098.

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