Investigators led by Navdeep Chandel, Ph.D., have made significant strides in understanding how mitochondrial metabolism influences T-cell function. Their recent study, published in Nature Immunology, reveals that mitochondria play a crucial role in supporting T-cell proliferation and preventing T-cell exhaustion, particularly in the context of cancer and chronic infections.
The research team, based in the Division of Pulmonary and Critical Care at Northwestern University, found that the mitochondrial electron transport chain (ETC)—a series of protein complexes within mitochondria—facilitates the transfer of electrons and is vital for generating ATP, the primary energy currency of the cell. Previous work from the Chandel laboratory had established that mitochondrial ETC function is essential for the growth of CD8+ T-cells, which are critical in combating cancer and viral infections. However, the specific functions of the mitochondrial ETC that promote CD8+ T-cell responses had not been fully understood until now.
Mitochondrial Complex III’s Role
In this study, researchers engineered mice lacking mitochondrial complex III, one of the four complexes in the ETC. This complex is responsible for transporting electrons and delivering protons, thereby facilitating ATP generation and the production of reactive oxygen species (ROS) that serve as cell signaling molecules. The findings revealed that impaired function of mitochondrial complex III led to decreased cellular respiration and diminished signaling linked to ATP production.
Consequently, CD8+ T-cells in these deficient mice showed reduced proliferation in response to viral infections and experienced rapid exhaustion following acute antigen stimulation—a phenomenon previously only associated with chronic antigen exposure.
Chandel explained the implications of these findings, noting, “Every time you get a viral infection, you robustly respond to the virus and 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 highlighted that impaired mitochondrial complex III function also negatively impacted memory formation in CD8+ T-cells, which is essential for long-term immunity.
Exploring Alternative Pathways
To further investigate the pathways involved, the scientists introduced an alternative oxidase (AOX) protein derived from C. intestinalis into the CD8+ T-cells lacking mitochondrial complex III. AOX is capable of compensating for the absence of complex III without generating ROS. Although AOX restored cell metabolism and proliferation, it did not facilitate memory formation, indicating that ROS generation is integral to this process.
Dr. Elizabeth Steinert, the study’s lead author and a research assistant professor of Medicine, emphasized that the findings reveal more than just an immediate failure of cell survival. “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,” she stated.
Implications for Future Therapies
The research underscores the critical link between mitochondrial respiration and T-cell behavior, suggesting potential new avenues for targeted immunotherapies. Chandel noted, “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.”
As scientists continue to explore the complex relationships between metabolism and immune function, these findings pave the way for innovative treatments that could enhance the body’s ability to combat diseases, particularly in cancer and chronic infection scenarios. The study reinforces the notion that a deeper understanding of mitochondrial biology may be key to unlocking new therapeutic strategies.
For further details, refer to the study by Elizabeth M. Steinert et al., titled “Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate,” published in Nature Immunology in 2025.