mG-modified mt-tRF3b-LeuTAA regulates mitophagy and metabolic reprogramming via SUMOylation of SIRT3 in chondrocytes.

Biomaterials

Department of Sports Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Electronic address:

Published: March 2025

N7-methylguanosine (mG) modification is one of the most prevalent RNA modifications, and methyltransferase-like protein-1 (METTL1) is a key component of the mG methyltransferase complex. METTL1-catalyzed mG as a new RNA modification pathway that regulates RNA structure, biogenesis, and cell migration. Increasing evidence indicates that mG modification has been implicated in the pathophysiological process of osteoarthritis (OA). However, the underlying molecular mechanisms of mG modification remains incompletely elucidated during the progression of OA. Here we found that METTL1 and mG levels were markedly increased in OA chondrocytes. In addition, METTL1-mediated mG modification upregulated mt-tRF3b-LeuTAA expression to exacerbate chondrocyte degeneration. Mechanistically, mt-tRF3b-LeuTAA decreased the SUMO-specific protease 1 (SENP1) protein expression and upregulated the level of sirtuin 3 (SIRT3) SUMOylation to inhibit PTEN induced kinase 1 (PINK1)/Parkin-mediated mitochondrial mitophagy. Intra-articular injection of PMC-tRF3b-LeuTAA inhibitor (Polyamidoamine-polyethylene glycol surface-modified with Minimal self-peptides and Chondrocyte-affinity peptides, PMC) attenuated destabilization of the medial meniscus (DMM) mouse cartilage degeneration in vivo. Our study demonstrates that METTL1/mG/mt-tRF3b-LeuTAA axis accelerate cartilage degradation by inhibiting mitophagy and promoting mitochondrial dysfunction through SIRT3 SUMOylation, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for OA treatment.

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http://dx.doi.org/10.1016/j.biomaterials.2024.122903DOI Listing

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