PO-02-124 MITOCHONDRIAL GLYCEROL-3-PHOSPHATE DEHYDROGENASE ACTS AT THE CROSSROAD OF METABOLISM REPROGRAMMING IN NON-VALVULAR ATRIAL FIBRILLATION: INDICATION FROM MULTI-OMICS ANALYSIS OF HUMAN AF MYOCARDIAL TISSUE

Abstract

Metabolic remodeling has been known to play an important role in the development of atrial fibrillation(AF). Recent studies have shown prominent mitochondrial metabolic changes of atrium, which have significant impact on the electrical signaling and structural remodeling of atrium. However, there is limited data on AF metabolic remodeling from multi-omics analysis of human myocardial tissue. In addition, the metabolism-related hub gene and pathways are not completely known. We aimed to explore the mitochondrial metabolism reprogrammed in AF, and describe the key dysregulated molecules of AF patients, as well as related metabolic pathways. In-hospital patients diagnosed with AF from 2019 to 2022 were enrolled. Left atrial appendages were harvested from AF patients undergoing cardiovascular surgery and matched ones from healthy donors with sinus rhythm(SR). Metabolomics and proteomics were then performed and analyzed. Moreover, biostatistical analysis was done for further identification. Heart tissue samples were harvested from 10 persistent non-valvular AF patients (Table1) and 10 matched SR samples from healthy donors. In metabolomics analysis, 113 metabolites were up-regulated and 10 were down-regulated (Panel A), where multiple pathways related to amino acid and glycolipid metabolism were enriched (Panel B). After correlation analysis between the differentially expressed proteins and metabolites, mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) was found crucial in AF patients in both positive- and negative-ionized mode (MCC score=16 and MCC score=6 respectively)(Panel C-D), which locates in the inner membrane of mitochondria and participates in cardiac mitochondrial function and glucolipid homeostasis. Proteomics revealed that the mitochondrial metabolism demonstrated marked difference in AF hearts than SR, especially the oxidative phosphorylation (NES=-1.73)(Panel E), ATP biosynthetic process (NES:-2.29), NADH dehydrogenase (NES:-2.36) etc., which were closely related to the function of mGPDH. The expression level of mGPDH was associated with multiple pathways related to cardiac structural remodeling using gene set variation analysis, which was further validated by external database (Panel F). Mitochondrial metabolism underwent prominent reprogramming in AF. mGPDH may participate in the development of AF via regulating mitochondrial metabolism and contribute to atrial remodeling, which could be considered as a a novel target for AF treatment.