Key result
Decreased HXK1 K418hib in atrial fibrillation reduced ATP production, increased KATP channel current, and shortened action potential duration, providing a metabolic mechanism for arrhythmogenesis.
Why the study?
Post-translational modifications are crucial epigenetic mechanisms, but the role of lysine 2-hydroxyisobutyrylation (Khib) in atrial fibrillation remains unknown.
Decreased HXK1 K418hib in atrial fibrillation alters energy metabolism and increases KATP channel current, providing a novel epigenetic mechanism for AF pathogenesis.
Atrial fibrillation (AF) is the most common form of arrhythmia and is a growing clinical problem. Post-translational modifications (PTMs) constitute crucial epigenetic mechanisms but modification of lysine 2-hydroxyisobutyrylation (Khib) in AF is still unknown. This study aimed to investigate the role and mechanism of Khib in AF. PTM proteomics was applied in the human atrial tissue from AF and sinus rhythm patients with heart valve disease during cardiac surgery to identify the Khib sites. The functional changes of differential modification sites were further validated at the cellular level. Cellular electrophysiology was performed to record the ion channel current and action potential duration (APD). The modification of 124 Khib sites in 35 proteins and 67 sites in 48 proteins exhibited significant increase or decrease in AF compared to sinus rhythm. Ten Khib sites were included in energy metabolism-related signaling pathways (HXK1, TPIS, PGM1, and ODPX in glycolysis; MDHC and IDH3A in tricarboxylic acid cycle; NDUS2, ETFB, ADT3, and ATPB in oxidative respiratory chain). Importantly, decreased HXK1 K418hib regulated by HDAC2 attenuated the original chemical binding domain between HXK1 and glucose, inhibited the binding ability between HXK1 and glucose, and reduced catalytic ability of the enzyme, resulting in low production of glucose-6-phosphate and ATP. Further, it also increased Kir6.2 protein and the current of KATP channel, and decreased APD. This study demonstrates the importance of Khib to catalysis of HXK1 and reveals molecular mechanisms of HXK1 K418hib in AF, providing new insight into strategies of AF.
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Hou et al. (2025) studied Atrial Fibrillation (n=26). Lysine 2-hydroxyisobutyrylation (Khib) profiling / HXK1 K418hib mutation (in vitro) vs. Sinus rhythm (SR) / Wild-type HXK1 was evaluated on Differentially expressed Khib sites and KATP channel current. Decreased HXK1 K418hib in atrial fibrillation reduced ATP production, increased KATP channel current, and shortened action potential duration, providing a metabolic mechanism for arrhythmogenesis.
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