Mitochondrial transplantation alleviates acute pancreatitis by suppressing macrophage necroptosis

Acute pancreatitis (AP) is a multifactorial disease in which mitochondrial dysfunction plays a key role by triggering inflammatory cascades and necrotic cell death. Mitochondrial transplantation has been reported to alleviate AP, however its underlying mechanisms remain unclear. To investigate the effect of mitochondrial transplantation on macrophage during AP, we stimulated macrophages with supernatant of damaged pancreatic acinar cells to mimic the inflammatory microenvironment. Upon stimulation, macrophages exhibited an enhanced capacity to internalize exogenous mitochondria. These exogenous mitochondria restored mitochondrial function in damaged macrophages by maintaining mitochondrial membrane potential, suppressing excessive reactive oxygen species production, and restoring ATP levels. Furthermore, mitochondria transplantation significantly inhibited macrophages necroptosis, as evidenced by the decreased protein expression and phosphorylation levels of the necroptosis markers RIPK1 and MLKL in macrophages and pancreatic tissue, and decreased cell necrosis. In terms of inflammation, exogenous mitochondria suppressed macrophage polarization toward the pro-inflammatory M1 phenotype and reduced the expression of pro-inflammatory cytokines. Collectively, these findings demonstrate that macrophage-centered inflammatory regulation constitutes a central mechanism underlying the therapeutic effects of mitochondrial transplantation in AP, providing a theoretical foundation for developing mitochondria-based therapeutic strategies.