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

Adv Sci (Weinh). 2024 Feb;11(5):e2303664. doi: 10.1002/advs.202303664. Epub 2023 Nov 21.


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.

Keywords: CD4+ T cells; adaptive immunity; aging immunology; immunometabolism; mitochondrial dysfunction.

MeSH terms

  • Aged
  • Aging*
  • Animals
  • CD4-Positive T-Lymphocytes
  • Humans
  • Mice
  • Mitochondria
  • Mitochondrial Diseases*
  • T-Lymphocytes, Regulatory