Increased COX6A2 promotes pancreatic β-cell apoptosis and is suppressed in diabetic GK rats after Roux-en-Y gastric bypass

Roux-en-Y gastric bypass (RYGB) has been shown to inhibit β-cell apoptosis, but the underlying mechanisms are not yet fully understood. Cytochrome c oxidase subunit 6A2 (COX6A2) is expressed in β-cells. Here, we sought to investigate the role of COX6A2 in β-cell apoptosis, especially following RYGB. We found that RYGB significantly reduced β-cell apoptosis, accompanied by decreased COX6A2 expression in islets from diabetic Goto-Kakizaki (GK) rats. It is noteworthy that overexpression of COX6A2 promoted β-cell apoptosis, whereas COX6A2 deficiency suppressed it, suggesting the pro-apoptotic role of COX6A2 in β-cells. Mechanistically, increased COX6A2 interacted with and upregulated the expression of cyclophilin D (CypD), facilitating the release of cytochrome c from mitochondria to the cytoplasm, thereby promoting β-cell apoptosis. Furthermore, high-glucose-activated ChREBP epigenetically regulated COX6A2 expression by recruiting histone acetyltransferase p300 to augment histone H3 acetylation at the Cox6a2 promoter, a process inhibited by GLP-1 signaling. Given that RYGB enhances GLP-1 signaling, RYGB is likely to deactivate ChREBP by boosting GLP-1/PKA signaling, thereby reducing COX6A2 expression in islets from GK rats. These findings highlight the crucial role of the GLP-1/PKA/ChREBP axis-controlled COX6A2 in β-cell apoptosis, revealing a previously unrecognized mechanism underlying the reduction in β-cell apoptosis induced by RYGB.