Extracellular Delivery of Functional Mitochondria Rescues the Dysfunction of CD4⁺ T Cells in Aging

Mitochondrial dysfunction alters cellular metabolism, increases tissue oxidative stress, and may be principal to the dysregulated signaling and function of CD4⁺ T lymphocytes in the elderly. In this proof of principle study, it is investigated whether the transfer of functional mitochondria into CD4⁺ T cells that are isolated from old mice (aged CD4⁺ T cells), can abrogate aging-associated mitochondrial dysfunction, and improve the aged CD4⁺ T cell functionality. The results show that the delivery of exogenous mitochondria to aged non-activated CD4⁺ T cells led to significant mitochondrial proteome alterations highlighted by improved aerobic metabolism and decreased cellular mitoROS. Additionally, mito-transferred aged CD4⁺ T cells showed improvements in activation-induced TCR-signaling kinetics displaying markers of activation (CD25), increased IL-2 production, enhanced proliferation ex vivo. Importantly, immune deficient mouse models (RAG-KO) showed that adoptive transfer of mito-transferred naive aged CD4⁺ T cells, protected recipient mice from influenza A and Mycobacterium tuberculosis infections. These findings support mitochondria as targets of therapeutic intervention in aging.