Improving Cardiac Resilience to Ischemia/Reperfusion: The Role of Butyrate in Mitochondrial and Metabolic Recovery

BackgroundCardiac transplantation is limited by a persistent shortage of donor organs. While hearts donated after circulatory death (DCD) could expand donors pool, their use is hindered by high rates of primary graft dysfunction (PGD) due to ischemia/reperfusion (I/R)-induced metabolic injury. Here, we investigate the therapeutic potential of the short-chain fatty acid butyrate (BT) to restore metabolic function in cardiomyocytes following I/R. MethodAdult human ventricular cardiomyocytes were used for in vitro cell perfusion (IVCP). Following a period of warm ischemia, butyrate (BT) was introduced into a prechilled UW solution to mimic the standard in situ cold flush performed during heart explant. Cells were then reperfused with cultural media for 1h at 37{degrees}C, after which both cells and perfusate were harvested for spectrometric metabolite profiling and molecular analyses using standard methods. ResultsBT reprograms cardiac substrate use from glucose to BT, enhancing mitochondrial oxidative phosphorylation and ATP production, as evidenced by increased lactate clearance and upregulated mitochondrial BT-oxidation enzymes. This metabolic shift restores redox balance by elevating NAD+/NADPH pool and reducing ADP/ATP ratio, while suppressing histone deacetylation and promoting gene expression linked to mitochondrial biogenesis, damage repair, recycling, and turnover via enhanced mitofusion and PINK1/Parkin-mediated mitophagy. BT subsequently reduces mitochondrial ROS, enhances electron transport chain activity, and preserves oxidative phosphorylation, thereby lowering caspase-3/7 activity, preventing apoptosis, and promoting cardiomyocyte metabolic recovery. ConclusionBT restores mitochondrial and metabolic function, preserves ATP synthesis after I/R injury, and mitigates metabolic maladaptation, offering strong potential to improve cardiac viability, graft function, and transplantation outcomes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/661163v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@82ab11org.highwire.dtl.DTLVardef@acffeborg.highwire.dtl.DTLVardef@1d5b958org.highwire.dtl.DTLVardef@7b4ca1_HPS_FORMAT_FIGEXP M_FIG Improving Cardiac Resilience to Ischemia/Reperfusion: The Role of Butyrate in Mitochondrial and Metabolic Recovery C_FIG