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

Lysine β-hydroxybutyrylation (Kbhb) is associated with energy regulation and mitochondrial function, and its role in sepsis-induced heart dysfunction has not been elucidated.

Reveals the extensive effects of Kbhb in sepsis-induced heart dysfunction and identifies the potential targets.

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.

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. 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 the specific promoter. Mechanistically, histone deacetylase 1 inhibited SUCLA2 Kbhb at K444 residue.

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.