Background & Aim Osteoarthritis (OA) is the most frequent joint disease worldwide with yet no known disease modifying drugs. In OA chondrocytes (OAC), the dysregulation of the metabolic biosensors that control mitochondrial biogenesis accounts for decreased numbers of mitochondria (MT) and reduced ATP levels in OA. Recently, our group evidenced that natural and artificial MT transfer (MitoT) from MSCs, convey potent metabolic and functional effects on target T cells, controlling organ damage and survival in an in-vivo model of inflammatory disease. In the present work, the effects of MitoT on the OAC phenotype is assessed in a coculture of MT-labelled MSCs with OAC. Methods, Results & Conclusion MitoT was evidenced as early as 4hrs and reached 97% after 24 hours. Cytochalasin B inhibition pointed to a tunneling Nanotubes (TNT)-dependent mechanism. The impact of MitoT, isolated from other effects of the MSC secretome was assessed in OACs incubated solely with MSC derived MT. FACS analysis revealed the internalization of exogenous MT with dose-dependent uptakes of MT equivalent to MSC:OAC ratios of 1:10, 1:5 and 1:1, with averages of 20.1%, 29.4% and 91.7% MitoTpos target OACs, respectively. Functional effect of the MitoT was assessed in readouts including (a) immunosuppression assays, where MitoTpos OAC induced only a slight change in PBMCs proliferation; (b) metabolic activity measured by WST-1 demonstrating an increase in the metabolic activity of MitoTpos OACs; (c) ROS-regulating autophagy gene expression levels showing a significant increase in SOD2 and Redd1mRNA levels in MitoTpos cells and (d) resistance to oxidative stress, assessed following H2O2 treatment, that revealed a protective effect of MitoT (15% reduction of dead cells). Furthermore, the intracellular fate of donated MT was evaluated with MT specific SNPs from the D-loop region. Using the amplification refractory mutation system (ARMS), a unique PCR product for MSC-derived MT was identified for at least 9 days in the target OACs. In conclusion, OAC were shown to be highly permissive for MT donation. The MitoT effect included an increase of metabolic activity and oxidative stress resistance that was correlated with an upregulation of SOD-2 expression. The biodistribution and efficacy of intraarticular injection of MT are currently being investigated in an OA mouse model. The MitoT induced reversal of the metabolic dysfunction typical of OACs might open new avenues to the understanding and treatment of OA.