Exosomal delivery of GrpE-like 1 from synovial mesenchymal stem cells activates PINK1-mediated mitophagy for cartilage repair in osteoarthritis.

GrpE-like 1 (GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells (SMSC) prevent mitochondrial dysfunction associated with osteoarthritis (OA) by activating PINK1-mediated mitophagy, restoring chondrocyte function, and preserving the extracellular matrix both in vitro and in vivo. Bioinformatics analysis of human OA datasets identified GRPEL1 as a mitophagy-related gene that is downregulated in OA. Exosomes enriched with GRPEL1 derived from SMSCs enhanced mitochondrial membrane potential and ATP production, reduced lipid peroxidation and reactive oxygen species, increased mitophagy markers (PINK1, Parkin, LC3-II/I), decreased p62 levels, and alleviated cartilage degeneration in a rat destabilization model. A causal role for mitophagy is supported by co-immunoprecipitation experiments confirming a GRPEL1-PINK1 interaction, and by PINK1 knockdown, which diminishes the protective effects of GRPEL1. These findings suggest that exosomes enriched with GRPEL1 derived from SMSCs represents a promising disease-modifying approach for OA by targeting mitochondrial quality control.