Deficiency of FUNDC1-mediated mitophagy impairs macrophages immunometabolism to drive Sepsis-induced...

Sepsis is a dysregulated host immune response to pathogen infection, characterized by an initial acute hyperinflammatory response followed by persistent immunosuppression. The immunosuppressive phase of sepsis is characterized by a marked impairment in the capacity of monocytes/macrophages to produce pro-inflammatory cytokines, a dysfunction linked to severe mitochondrial metabolic defects. Mitophagy is a crucial cellular process that regulates macrophage inflammation by maintaining mitochondrial homeostasis. FUN14domain- containing 1 (FUNDC1) is a known mitophagy receptor, but its role in macrophages during sepsis-induced immunosuppression remains unclear. In this study, we found that FUNDC1-mediated mitophagy is suppressed in immunosuppressive macrophages. Furthermore, both FUNDC1 knockdown and a cell-penetrating FUNDC1-inhibitory peptide P (CPP-P) further suppressed pro-inflammatory cytokines production in immunosuppressive macrophages. Mechanistic studies demonstrated that suppressing FUNDC1-dependent mitophagy exacerbates metabolic dysfunction of immunosuppressive macrophages. Additionally, CPP-P-treated mice exhibit reduced pro-inflammatory cytokines release and impaired bacterial clearance, resulting in exacerbated lung tissue damage and elevated mortality during the immunosuppressive phase of sepsis. Collectively, our study demonstrates that suppression of FUNDC1-mediated mitophagy in macrophages contributes to the immunocompromised state in sepsis and reveals potential therapeutic targets.