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Theranostics 2024; 14(4):1561-1582. doi:10.7150/thno.92650 This issue Cite

Research Paper

The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation

Rongjun Zou1,2,3#, Wanting Shi4#, Xing Chang5#, Miao Zhang1,2,3, Songtao Tan1,2,3, Ruibing Li6, Hao Zhou6, Yukun Li7✉, Ge Wang1,2,3✉, Weihui Lv8✉, Xiaoping Fan1,2,3✉

1. Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, the Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong, China.
2. State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou 510120, Guangdong, China.
3. Guangdong Provincial Key Laboratory of TCM Emergency Research, Guangzhou 510120, Guangdong, China.
4. Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China.
5. Guang'anmen Hospital of Chinese Academy of Traditional Chinese Medicine, Beijing, China.
6. Department of Clinical Laboratory Medicine, The First Medical Centre, Medical School of Chinese People's Liberation Army, Beijing, China.
7. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
8. State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
#The first three authors contributed equally to this article.

✉ Corresponding authors: Yukun Li, email: loren.licom; Ge Wang, email: wanggeedu.cn; Weihui Lv, email: weihui.luedu.cn; Xiaoping Fan, email: fukui-hansoncom.

Citation:
Zou R, Shi W, Chang X, Zhang M, Tan S, Li R, Zhou H, Li Y, Wang G, Lv W, Fan X. The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation. Theranostics 2024; 14(4):1561-1582. doi:10.7150/thno.92650. https://www.thno.org/v14p1561.htm
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Abstract

Graphic abstract

Rationale: The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) promotes pathological mitochondrial fission during septic acute kidney injury. The mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) is a mitochondria-derived peptide that exhibits anti-inflammatory properties during cardiovascular illnesses. We explored whether endotoxemia-induced myocardial microvascular injury involved DNA-PKcs and MOTS-c dysregulation.

Methods: To induce endotoxemia in vivo, endothelial cell-specific DNA-PKcs-knockout mice were injected intraperitoneally with a single dose of lipopolysaccharide (10 mg/kg) and evaluated after 72 h.

Results: Lipopolysaccharide exposure increased DNA-PKcs activity in cardiac microvascular endothelial cells, while pharmacological inhibition or endothelial cell-specific genetic ablation of DNA-PKcs reduced lipopolysaccharide-induced myocardial microvascular dysfunction. Proteomic analyses showed that endothelial DNA-PKcs ablation primarily altered mitochondrial protein expression. Verification assays confirmed that DNA-PKcs drastically repressed MOTS-c transcription by inducing mtDNA breaks via pathological mitochondrial fission. Inhibiting MOTS-c neutralized the endothelial protective effects of DNA-PKcs ablation, whereas MOTS-c supplementation enhanced endothelial barrier function and myocardial microvascular homeostasis under lipopolysaccharide stress. In molecular studies, MOTS-c downregulation disinhibited c-Jun N-terminal kinase (JNK), allowing JNK to phosphorylate profilin-S173. Inhibiting JNK or transfecting cells with a profilin phosphorylation-defective mutant improved endothelial barrier function by preventing F-actin depolymerization and lamellipodial degradation following lipopolysaccharide treatment.

Conclusions: DNA-PKcs inactivation during endotoxemia could be a worthwhile therapeutic strategy to restore MOTS-c expression, prevent JNK-induced profilin phosphorylation, improve F-actin polymerization, and enhance lamellipodial integrity, ultimately ameliorating endothelial barrier function and reducing myocardial microvascular injury.

Keywords: DNA-PKcs, MOTS-c, JNK, profilin, lamellipodia, endothelial barrier, myocardial microvascular injury

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APA
Zou, R., Shi, W., Chang, X., Zhang, M., Tan, S., Li, R., Zhou, H., Li, Y., Wang, G., Lv, W., Fan, X. (2024). The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation. Theranostics, 14(4), 1561-1582. https://doi.org/10.7150/thno.92650.

ACS
Zou, R.; Shi, W.; Chang, X.; Zhang, M.; Tan, S.; Li, R.; Zhou, H.; Li, Y.; Wang, G.; Lv, W.; Fan, X. The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation. Theranostics 2024, 14 (4), 1561-1582. DOI: 10.7150/thno.92650.

NLM
Zou R, Shi W, Chang X, Zhang M, Tan S, Li R, Zhou H, Li Y, Wang G, Lv W, Fan X. The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation. Theranostics 2024; 14(4):1561-1582. doi:10.7150/thno.92650. https://www.thno.org/v14p1561.htm

CSE
Zou R, Shi W, Chang X, Zhang M, Tan S, Li R, Zhou H, Li Y, Wang G, Lv W, Fan X. 2024. The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation. Theranostics. 14(4):1561-1582.

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