Investigators have discovered how mitochondria support T-cell proliferation and prevent exhaustion in cancer and chronic infections. Led by Navdeep Chandel, PhD, and David W. Cugell, MD, a team found that mitochondrial electron transport chain (ETC) plays a crucial role in regulating T-cell response and proliferation.
The researchers used mice lacking mitochondrial complex III to study the effects of impaired ETC function on CD8+ T-cells, which play a key role in fighting cancer and viral infections. The results showed that deficient mitochondria led to decreased cellular respiration, reduced signaling molecules linked to ATP production, and diminished T-cell proliferation upon viral infection.
Interestingly, these cells also underwent rapid exhaustion upon acute antigen stimulation, contrary to previous observations where exhaustion occurred under chronic antigen stimulation. Furthermore, impaired mitochondrial complex III function reduced CD8+ T-cell memory formation, which helps immune cells persist after initial infection.
To investigate further, the scientists introduced an alternative oxidase protein into mitochondria-deficient CD8+ T-cells, revealing that this protein could complement the loss of complex III without generating reactive oxygen species. While AOX restored cell metabolism and proliferation, it did not restore memory formation, indicating a link between ROS generation and memory cell development.
These findings suggest that mitochondrial respiration is essential for T-cell proliferation and memory formation, highlighting the importance of targeting mitochondria in therapeutic strategies. As Chandel noted, “This tells you that mitochondrial metabolism prevents exhaustion, mitochondrial metabolism supports proliferation, and mitochondrial ROS is necessary to make memory.” The study has implications for the development of new immunotherapies and sheds light on the critical role of mitochondria in T-cell biology.
Source: https://news.feinberg.northwestern.edu/2025/07/24/mitochondria-support-t-cells-proliferation-and-memory-formation