Lysine 2-hydroxyisobutyrylation of HXK1 alters energy metabolism and K channel function in the atrium from patients with atrial fibrillation.

BACKGROUND

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 (K) in AF is still unknown. This study aimed to investigate the role and mechanism of K in AF.

METHODS

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 K 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).

RESULTS

The modification of 124 K sites in 35 proteins and 67 sites in 48 proteins exhibited significant increase or decrease in AF compared to sinus rhythm. Ten K 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 K418 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 K channel, and decreased APD.

CONCLUSIONS

This study demonstrates the importance of K to catalysis of HXK1 and reveals molecular mechanisms of HXK1 K418 in AF, providing new insight into strategies of AF.