Mitochondrial Metabolism's Crucial Role in T-Cell Proliferation

In a groundbreaking study published in *Nature Immunology* on July 29, 2025, researchers at Northwestern University have elucidated the critical role of mitochondrial metabolism in supporting T-cell proliferation and preventing cellular exhaustion during cancer and chronic infections. The research team, led by Dr. Navdeep Chandel, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care, highlights how the mitochondrial electron transport chain (ETC) facilitates energy production and signaling necessary for optimal T-cell function.

The significance of this research lies in its potential to inform the development of novel immunotherapies aimed at enhancing T-cell responses against malignancies and persistent viral infections. Previous investigations by the Chandel laboratory had established the necessity of mitochondrial ETC function for the proliferation of CD8+ T-cells, which play a vital role in the immune response by targeting cancerous cells and viral pathogens. However, the specific functions of the ETC that contribute to T-cell activation and proliferation remained largely unexplored until now.

In the current study, the researchers engineered mice that lacked mitochondrial complex III, one of four complexes integral to the ETC. This manipulation allowed the team to observe the effects of compromised mitochondrial function on CD8+ T-cells. They discovered that the absence of complex III resulted in diminished cellular respiration and a reduction in the production of reactive oxygen species (ROS), which are crucial signaling molecules for T-cell activation. Consequently, these deficient T-cells exhibited impaired proliferation in response to viral infections and a surprising onset of rapid exhaustion following acute antigen stimulation, a phenomenon previously attributed to chronic antigen exposure.

Dr. Chandel explained, "Every time you get a viral infection, you robustly respond to the virus and you clear it out, but you have a few memory T-cells that are sitting around that if you get the same virus again, they proliferate quickly to protect you.” The study further indicated that impaired mitochondrial complex III function hindered the formation of CD8+ T-cell memory, a critical component of the immune system that enables it to respond swiftly to previously encountered pathogens.

To delve deeper, the researchers introduced an alternative oxidase (AOX) protein derived from *Ciona intestinalis* into the mitochondrial complex III-deficient CD8+ T-cells. AOX compensates for the loss of mitochondrial complex III without producing ROS. While AOX successfully mitigated T-cell exhaustion and restored metabolic activity and proliferation, it did not facilitate memory formation, indicating that ROS generation remains essential for this process. Lead author Dr. Elizabeth Steinert, a research assistant professor of Medicine, stated, "We saw memory precursor marker expression by those cells, showing that it’s not just an immediate death signal, but it’s a failure to form a terminal memory cell that can stick around."

The findings underscore the importance of mitochondrial respiration in both T-cell proliferation and memory formation, suggesting potential avenues for therapeutic strategies that target mitochondrial function in immune cells. Dr. Chandel emphasized, "This tells you that mitochondrial metabolism prevents exhaustion, mitochondrial metabolism supports proliferation, and mitochondrial ROS is necessary to make memory. That really puts mitochondria at the center of T-cell biology, so maybe we should think about therapies that target mitochondria to rejuvenate them."

This research represents a significant advancement in understanding T-cell biology and opens new possibilities for improving immunotherapy outcomes in cancer and chronic infections. As the landscape of cancer treatment continues to evolve, strategies that enhance mitochondrial function could play a pivotal role in developing more effective therapies to combat these diseases.

For further information, please refer to the original publication: Steinert EM, Furtado Bruza B, Danchine VD, et al. Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate. *Nat Immunol*. 2025. doi:10.1038/s41590-025-02202-x.