Targeting PGAM5-Drp1 axis modulates mitochondrial dynamics and inhibits pancreatic acinar cell necroptosis in severe acute pancreatitis

Abstract

Severe acute pancreatitis (SAP) is a high-mortality disease characterized by extensive pancreatic necrosis and uncontrolled inflammation. Mitochondrial dysfunction and pancreatic acinar cells (PACs) necroptosis are critical pathological events in SAP, while the role of the mitochondrial protein phosphoglycerate mutase family member 5 (PGAM5) in SAP remains poorly defined. This study aimed to explore the function and mechanism of PGAM5 in SAP pathogenesis. PGAM5 expression was examined in pancreatic tissues of SAP mice and clinical pancreatitis samples. Bioinformatics analysis was used to identify alterations in mitochondrial dynamics and necroptosis pathways. In vitro, PGAM5 knockdown was performed in PACs to detect dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, mitochondrial function, reactive oxygen species (ROS) accumulation and cell necroptosis. The direct interaction between PGAM5 and Drp1 was validated. In vivo, a PGAM5-specific inhibitor was applied to evaluate pancreatic injury in SAP mice. PGAM5 expression was significantly upregulated in both SAP mouse tissues and human pancreatitis samples. PGAM5 knockdown inhibited Drp1-mediated mitochondrial fission, restored mitochondrial membrane potential, decreased ROS accumulation, and suppressed PACs necroptosis. A direct binding interaction existed between PGAM5 and Drp1. In vivo inhibition of PGAM5 effectively alleviated pancreatic injury in SAP mice. The PGAM5–Drp1 axis induces mitochondrial dysfunction and promotes PACs necroptosis, thereby contributing to SAP progression. Unlike previous studies focused mainly on downstream inflammatory and necroptotic signaling, the present work associates the PGAM5–Drp1 axis with SAP-related mitochondrial damage, providing a potential target for SAP intervention.