High concentrations of L-lysine cause mitochondrial damage and necrosis in isolated pancreatic acinar cells

Abstract

Intraperitoneal administration of high doses of basic amino acids, such as L-lysine (L-Lys), L-arginine (L-Arg) or L-ornithine (L-Orn) induces acute pancreatitis in rodents. Although the exact mechanism of their action is not fully understood, the role of mitochondria has been implicated. We aimed to investigate the effects of basic amino acids, particularly L-Lys, on isolated pancreatic acinar cells. Isolated mouse or rat pancreatic acinar cells were treated with high concentrations (10–60 mM) of L-Lys, L-Arg or L-Orn. The morphology of acinar mitochondria was observed by electron microscopy. The function of mitochondria was assessed by mitochondrial membrane potential (∆Ψm) and cellular ATP level measurements. Changes in intracellular Ca²⁺ concentration ([Ca²⁺]_i), trypsin activity and cellular viabilities were also determined. Treatment of acinar cells with L-Lys caused mitochondrial swelling. L-Lys and L-Orn dramatically decreased ∆Ψm after 6 h of treatment, whereas L-Arg reduced ∆Ψm after 3 h of treatment. Intracellular ATP levels were also reduced by basic amino acids. L-Lys did not alter [Ca²⁺]_i and did not induce early trypsinogen activation. Furthermore, L-Lys administration primarily caused acinar necrosis. Overall, L-Lys primarily damaged pancreatic acinar mitochondria and caused necrotic cell death without affecting [Ca²⁺]_i.