Lineage‐Mismatched Mitochondrial Replacement in an Inducible Mitochondrial Depletion Model Effectively Restores the Original Proteomic Landscape of Recipient Cells

The therapeutic potential of mitochondrial transfer has been recently demonstrated in a number of preclinical and clinical studies. However, the molecular mechanisms underpinning the success of mitochondrial transfer, including how exogenous mitochondria may influence the cellular proteomic landscape, are largely unknown. Using a mitochondrial depletion model designed to eliminate endogenous cellular mitochondria, we evaluated proteomic profiles in cells following exogenous mitochondrial transplantation. Our data demonstrate that exogenous mitochondrial transfer does not significantly alter the proteomic profile in non-depleted host cells, and largely rescues the aberrant proteome of mitochondrial-depleted cells following internalization. Our data add to a growing body of supportive evidence suggesting that transfer of exogenous mitochondria does not disrupt or perturb the intracellular landscape, and further demonstrate that mitochondrial transfer is capable of restoring cellular phenotype in an induced-depletion model.