HDAC1-mediated SUCLA2 lysine β-hydroxybutyrylation modulates myocardial mitochondrial function in sepsis-induced heart dysfunction.
8 affiliations
- 1Department of Pediatrics, PICU, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
- 2Institute for Clinical Medical Research, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China.
- 3Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200240, China.
- 4Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China.
- 5Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
- 6Department of Pediatrics, PICU, Shengjing Hospital of China Medical University, Shenyang, 110004, China. Electronic address: [email protected].
- 7Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: [email protected].
- 8Department of Pediatrics, PICU, Shengjing Hospital of China Medical University, Shenyang, 110004, China. Electronic address: [email protected].
Abstract
Background
Lysine β-hydroxybutyrylation (Kbhb) is associated with energy regulation and mitochondrial function, and its role in sepsis-induced heart dysfunction has not been elucidated.Objectives
Reveals the extensive effects of Kbhb in sepsis-induced heart dysfunction and identifies the potential targets.Methods
A septic heart dysfunction rat model was induced by lipopolysaccharide intraperitoneal injection. Proteomic and β-hydroxybutyrylomic analyses were conducted to assess alterations in Kbhb between cardiac tissues from the control and lipopolysaccharide rats. Putative regulatory proteins were identified by leveraging a multifaceted hybrid learning framework combined with protein language models. Lysine to arginine (R) mutation was made to mimic decreased Kbhb levels. Transcriptomic analysis was further performed to predict the potential downstream mechanisms.Results
Succinate-CoA Ligase ADP-Forming Subunit Beta (SUCLA2) was selected because of its role in mitochondrial function, and the Kbhb level at the K444 site was significantly different. Decreased Kbhb level at K444 of SUCLA2 was confirmed in septic cardiac tissues and lipopolysaccharide-treated H9c2 cardiomyocytes using specific antibody. SUCLA2K444R mutant reversed the protective effects of SUCLA2WT on mitochondrial function in lipopolysaccharide-treated H9c2 cardiomyocytes, accompanied by decreased succinyl-CoA synthetase activity, reduced mitochondrial membrane potential, suppressed adenosine triphosphate production, and increased reactive oxygen species accumulation. The aggravating effects of the SUCLA2K444R mutant on septic heart dysfunction were confirmed in vivo using the specific promoter. Mechanistically, histone deacetylase 1 inhibited SUCLA2 Kbhb at K444 residue.Conclusions
Reduced SUCLA2 Kbhb level at K444 site aggravates myocardial mitochondrial dysfunction, leading to sepsis-induced heart dysfunction. This study reveals a novel function of Kbhb in sepsis-induced heart dysfunction and elucidates the mechanism of SUCLA2 K444 Kbhb.
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BibTeX
@article{wen2026hdac1mediated,
title = {{HDAC1-mediated SUCLA2 lysine β-hydroxybutyrylation modulates myocardial mitochondrial function in sepsis-induced heart dysfunction.}},
author = {Ri Wen and Wanshan Ning and Xin-Mei Huang and Peng-Hui Hao and Jingjing Yang and Wei Liu and Yu-Hang Yang and Chun-Feng Liu and Ni Yang and Yaping Guo and Tie-Ning Zhang},
journal = {Redox biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104431},
url = {https://europepmc.org/article/MED/42874129},
note = {CC BY},
}
RIS
TY - JOUR
TI - HDAC1-mediated SUCLA2 lysine β-hydroxybutyrylation modulates myocardial mitochondrial function in sepsis-induced heart dysfunction.
AU - Ri Wen
AU - Wanshan Ning
AU - Xin-Mei Huang
AU - Peng-Hui Hao
AU - Jingjing Yang
AU - Wei Liu
AU - Yu-Hang Yang
AU - Chun-Feng Liu
AU - Ni Yang
AU - Yaping Guo
AU - Tie-Ning Zhang
PY - 2026
DA - 2026/10/08
JO - Redox biology
DO - 10.1016/j.redox.2026.104431
UR - https://europepmc.org/article/MED/42874129
AB - Background Lysine β-hydroxybutyrylation (Kbhb) is associated with energy regulation and mitochondrial function, and its role in sepsis-induced heart dysfunction has not been elucidated.Objectives Reveals the extensive effects of Kbhb in sepsis-induced heart dysfunction and identifies the potential targets.Methods A septic heart dysfunction rat model was induced by lipopolysaccharide intraperitoneal injection. Proteomic and β-hydroxybutyrylomic analyses were conducted to assess alterations in Kbhb between cardiac tissues from the control and lipopolysaccharide rats. Putative regulatory proteins were identified by leveraging a multifaceted hybrid learning framework combined with protein language models. Lysine to arginine (R) mutation was made to mimic decreased Kbhb levels. Transcriptomic analysis was further performed to predict the potential downstream mechanisms.Results Succinate-CoA Ligase ADP-Forming Subunit Beta (SUCLA2) was selected because of its role in mitochondrial function, and the Kbhb level at the K444 site was significantly different. Decreased Kbhb level at K444 of SUCLA2 was confirmed in septic cardiac tissues and lipopolysaccharide-treated H9c2 cardiomyocytes using specific antibody. SUCLA2K444R mutant reversed the protective effects of SUCLA2WT on mitochondrial function in lipopolysaccharide-treated H9c2 cardiomyocytes, accompanied by decreased succinyl-CoA synthetase activity, reduced mitochondrial membrane potential, suppressed adenosine triphosphate production, and increased reactive oxygen species accumulation. The aggravating effects of the SUCLA2K444R mutant on septic heart dysfunction were confirmed in vivo using the specific promoter. Mechanistically, histone deacetylase 1 inhibited SUCLA2 Kbhb at K444 residue.Conclusions Reduced SUCLA2 Kbhb level at K444 site aggravates myocardial mitochondrial dysfunction, leading to sepsis-induced heart dysfunction. This study reveals a novel function of Kbhb in sepsis-induced heart dysfunction and elucidates the mechanism of SUCLA2 K444 Kbhb.
SN - 2213-2317
ER -