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Int J Biol Sci 2023; 19(10):3143-3158. doi:10.7150/ijbs.84613 This issue Cite

Research Paper

VDAC2 malonylation participates in sepsis-induced myocardial dysfunction via mitochondrial-related ferroptosis

Han She1,2†, Lei Tan1,2†, Yuanlin Du2†, Yuanqun Zhou1, Ningke Guo1, Jun Zhang2, Yunxia Du1,2, Yi Wang1,2, Zhengbin Wu3, Chunhua Ma1, Qinghui Li1, Qingxiang Mao2, Yi Hu2✉, Liangming Liu1✉, Tao Li1✉

1. State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Department, Daping Hospital, Army Medical University, Chongqing400042, China
2. Department of Anesthesiology, Daping Hospital, Army Medical University, Chongqing400042, China
3. Department of Intensive care unit, Daping Hospital, Army Medical University, Chongqing400042, China
†These authors contributed equally to this work

✉ Corresponding authors: Tao Li, Liangming Liu and Yi Hu E-mail: lt200132com, lmliu62edu.cn, huyi921com Tel: +86-23-68757525 Fax: +86-23-68757525

Citation:
She H, Tan L, Du Y, Zhou Y, Guo N, Zhang J, Du Y, Wang Y, Wu Z, Ma C, Li Q, Mao Q, Hu Y, Liu L, Li T. VDAC2 malonylation participates in sepsis-induced myocardial dysfunction via mitochondrial-related ferroptosis. Int J Biol Sci 2023; 19(10):3143-3158. doi:10.7150/ijbs.84613. https://www.ijbs.com/v19p3143.htm
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Abstract

Graphic abstract

Sepsis-induced myocardial dysfunction (SIMD) is a prevalent and severe form of organ dysfunction with elusive underlying mechanisms and limited treatment options. In this study, the cecal ligation and puncture and lipopolysaccharide (LPS) were used to reproduce sepsis model in vitro and vivo. The level of voltage-dependent anion channel 2 (VDAC2) malonylation and myocardial malonyl-CoA were detected by mass spectrometry and LC-MS-based metabolomics. Role of VDAC2 malonylation on cardiomyocytes ferroptosis and treatment effect of mitochondrial targeting nano material TPP-AAV were observed. The results showed that VDAC2 lysine malonylation was significantly elevated after sepsis. In addition, the regulation of VDAC2 lysine 46 (K46) malonylation by K46E and K46Q mutation affected mitochondrial-related ferroptosis and myocardial injury. The molecular dynamic simulation and circular dichroism further demonstrated that VDAC2 malonylation altered the N-terminus structure of the VDAC2 channel, causing mitochondrial dysfunction, increasing mitochondrial ROS levels, and leading to ferroptosis. Malonyl-CoA was identified as the primary inducer of VDAC2 malonylation. Furthermore, the inhibition of malonyl-CoA using ND-630 or ACC2 knock-down significantly reduced the malonylation of VDAC2, decreased the occurrence of ferroptosis in cardiomyocytes, and alleviated SIMD. The study also found that the inhibition of VDAC2 malonylation by synthesizing mitochondria targeting nano material TPP-AAV could further alleviate ferroptosis and myocardial dysfunction following sepsis. In summary, our findings indicated that VDAC2 malonylation plays a crucial role in SIMD and that targeting VDAC2 malonylation could be a potential treatment strategy for SIMD.

Keywords: Sepsis, Malonylation, VDAC2, Ferroptosis, Malonyl-CoA

Citation styles

APA
She, H., Tan, L., Du, Y., Zhou, Y., Guo, N., Zhang, J., Du, Y., Wang, Y., Wu, Z., Ma, C., Li, Q., Mao, Q., Hu, Y., Liu, L., Li, T. (2023). VDAC2 malonylation participates in sepsis-induced myocardial dysfunction via mitochondrial-related ferroptosis. International Journal of Biological Sciences, 19(10), 3143-3158. https://doi.org/10.7150/ijbs.84613.

ACS
She, H.; Tan, L.; Du, Y.; Zhou, Y.; Guo, N.; Zhang, J.; Du, Y.; Wang, Y.; Wu, Z.; Ma, C.; Li, Q.; Mao, Q.; Hu, Y.; Liu, L.; Li, T. VDAC2 malonylation participates in sepsis-induced myocardial dysfunction via mitochondrial-related ferroptosis. Int. J. Biol. Sci. 2023, 19 (10), 3143-3158. DOI: 10.7150/ijbs.84613.

NLM
She H, Tan L, Du Y, Zhou Y, Guo N, Zhang J, Du Y, Wang Y, Wu Z, Ma C, Li Q, Mao Q, Hu Y, Liu L, Li T. VDAC2 malonylation participates in sepsis-induced myocardial dysfunction via mitochondrial-related ferroptosis. Int J Biol Sci 2023; 19(10):3143-3158. doi:10.7150/ijbs.84613. https://www.ijbs.com/v19p3143.htm

CSE
She H, Tan L, Du Y, Zhou Y, Guo N, Zhang J, Du Y, Wang Y, Wu Z, Ma C, Li Q, Mao Q, Hu Y, Liu L, Li T. 2023. VDAC2 malonylation participates in sepsis-induced myocardial dysfunction via mitochondrial-related ferroptosis. Int J Biol Sci. 19(10):3143-3158.

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