Work

HDAC1-mediated SUCLA2 lysine β-hydroxybutyrylation modulates myocardial mitochondrial function in sepsis-induced heart dysfunction

Year: 2026

Type: article

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 level. Transcriptomic analysis was further performed to predict the potential downstream mechanism. Results Succinate-CoA Ligase ADP-Forming Subunit Beta (SUCLA2) was selected because of its role in mitochondrial function, and the Kbhb levels of K444 site was significant difference. Decreased Kbhb level at K444 of SUCLA2 was confirmed in septic cardiac tissues and lipopolysaccharide-treated H9c2 cardiomyocytes using specific antibody. SUCLA2 K444R mutant reversed the protective effects of SUCLA2 WT 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 SUCLA2 K444R mutant on septic heart dysfunction were confirmed in vivo using specific promoter. Mechanistically, histone deacetylase 1 promoted 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.

Source: Redox Biology

DOI: 10.1016/j.redox.2026.104431