SIRT3-mediated mitophagy by deacetylating ATP5F1A involved in the protective effects of SIGMAR1/Sigma-1 receptor against ferroptosis and microvascular hyperpermeability in lipopolysaccharide-induced acute lung injury.

Summary

Using LPS-induced ALI models, the authors show that activating SIGMAR1 with PRE-084 suppresses endothelial ferroptosis and microvascular hyperpermeability, effects abolished by mitophagy inhibition. Mechanistically, a SIRT3-dependent deacetylation of ATP5F1A promotes mitophagy, linking mitochondrial quality control to ferroptosis resistance and barrier preservation.

Key Findings

• SIGMAR1 activation with PRE-084 reduces endothelial ferroptosis and microvascular hyperpermeability in LPS-induced ALI.
• Blocking mitophagy abrogates the protective effects of SIGMAR1 activation, implicating mitophagy as necessary.
• A mechanistic pathway involving SIRT3-mediated deacetylation of ATP5F1A triggers mitophagy that confers ferroptosis resistance.

Clinical Implications

While preclinical, the work prioritizes SIGMAR1/SIRT3-driven mitophagy and ferroptosis modulation as therapeutic strategies to preserve endothelial barrier integrity in ALI/ARDS.

Limitations

• Preclinical cellular and murine models may not fully recapitulate human ARDS pathophysiology.
• Potential off-target effects of PRE-084 and pathway complexity warrant careful translational validation.

Future Directions

Validate the SIGMAR1–SIRT3–ATP5F1A axis in human lung microvascular endothelium and ARDS biospecimens, and explore drug development targeting mitophagy/ferroptosis across diverse ALI etiologies.