Mitochondrial Dynamics and T-Cell Activation
The activation of T cells is a critical part of our adaptive immune system. T-cell activation requires massive increases in gene expression and cell proliferation, which is dependent on increased energy production. A research team at the Cancer Research UK Scotland Institute in Glasgow, led by Alison Galloway, Victoria H. Cowling and Tom MacVicar, examined RNA splicing mechanisms involved in T-cell activation. Mitochondria act as a signaling nexus in T cells, and they found that T cells regulate their energetic capacity by alternative splicing of proteins involved in mitochondrial fission and fusion to match the demands of T-cell activation. This study was recently published as a paper in Cell Reports.
More specifically, the team focused on the RNA cap methyltransferase 1 (CMTR1). This enzyme methylates the first nucleotide on mRNAs and U2 small nuclear RNA, part of the spliceosome. Using transcriptomics, they found a splicing module, regulated by CMTR1, that changes the protein isoforms of factors that control mitochondrial fission and fusion. CMTR1 promotes expression of protein isoforms that alter the balance between fusion and fission to produce longer mitochondria in activated T cells. Those longer organelles have greater respiratory capacity.
Thus, the researchers show that increasing CMTR1 levels increases oxidative phosphorylation and supports T-cell activation. This study further shows that mitochondria do more than just produce energy. It also adds to the knowledge of the immune system, the highly complex and crucial mechanisms for our health.
A conversation with Drs. Galloway and Cowling
MitoWorld: Can you give us an idea of the next steps for this research? For example, might you further examine how CMTR1 modulates splicing?
We are interested in how T cells function in tumours. Therapies that improve or support T-cell functions are proving successful in the treatment of many cancers. A limitation of these therapies is that T cells become “exhausted”, exhibiting features associated with loss of mitochondrial quality control, such as depolarized mitochondria and mitochondria with disrupted morphology of the cristae. By targeting CMTR1 and other RNA cap methyltransferases, it is possible that we can support mitochondria function in T cells.
MitoWorld: As you note, mitochondria are involved in many aspects of T-cell biology. Any thoughts on how they might regulate T-cell receptor (TCR) signaling strength, memory formation, or T-cell exhaustion?
Mitochondrial dynamics is a very exciting area in T-cell research. TCR signaling strength is increased by the migration of mitochondria to the immunological synapse—the site at which the TCRs are engaged with antigen/MHC complexes on the antigen-presenting cell. This process is facilitated by mitochondrial fission, which generates smaller, more mobile mitochondria and, thus, is very dependent on mitochondrial fission factors, such as DNM1L/DRP1. On the other hand, memory T cells are metabolically very dependent on oxidative phosphorylation. The longer, more complex mitochondrial networks generated by fusion have greater respiratory capacity, thus the generation and maintenance of memory T cells is very dependent on mitochondrial fusion factors, such as OPA1. Therefore, the proper regulation of T-cell activation, effector function, and memory formation depends on dynamic regulation of mitochondrial morphology, as well as metabolism. In exhausted T cells, we are seeing signs that mitochondrial dynamics have been disrupted, resulting in a buildup of depolarized mitochondria. This is linked to impaired mitophagy, the process by which damaged mitochondria are removed.
MitoWorld: T-cell activation requires careful coordination of gene activation in both the nucleus and mitochondria. Do you have any hypotheses about how this signaling is accomplished?
We think that the RNA cap methyltransferases play important roles in coordinating gene expression and energy production during T-cell activation. After T-cell activation, upregulation of the RNA cap methyltransferase, RNMT, co-ordinates gene expression programmes that results in ribosome production. Ribosomes are the most energy hungry component of the cell; it’s interesting that the genome evolved such that upregulation of another RNA cap methyltransferase—CMTR1—increases respiration during T-cell activation.
MitoWorld: There are hundreds to a few thousand mitochondria in each cell. Do you have any idea about the number or portion of mitochondria must be fused to change the energy production within the cell?
This is a tricky question! In our measurements of mitochondrial length in T cells, we saw a huge range in mitochondrial size with the longest measuring in at nearly 2.5 mm long and the shortest under 0.1 mm. Some of this variation will be due to the orientation of each mitochondrion during the microscopy, but it still indicates that there can be big differences between mitochondria within the same cell. There are still a lot of questions to answer around how the length of the mitochondria influences their metabolic activity.
MitoWorld: T-cell activation is obviously related to infections. Can you envision how your findings might inform therapeutic strategies?
Yes, there are several strategies that may improve or support T cells in tumours, focusing on mitochondria. Mitochondrial functionality could potentially be enhanced by engineering deregulated CMTR1 expression or increasing activating phosphorylation on CMTR1. Alternatively, the splicing modules which control mitochondria function could be more directly controlled in T-cell therapeutics.
MitoWorld: Why did you become interested in mitochondria in the first place? Which came first: mitochondria or the immune system?
VC: My first publication (2002!) was about cytochrome C-triggered caspase cascades. Beyond this, I think there is a fascinating relationship between mitochondria and ribosomes. Gene expression is dependent on energy production by mitochondria supporting energy-hungry ribosomes.
AG: For me, the immune system came first, but the mitochondria are making themselves very hard to ignore since they keep showing themselves to be key mediators of immune cell function!
Reference
Galloway A, Knop K, Gomez-Moreira C, Xavier V, Thomson S, Yoshikawa H, Suska O, Lukoszek R, Kaskar A, Lamond AI, MacVicar T, Cowling VH (2025) CMTR1 directs mitochondrial dynamics during T cell activation through epitranscriptomic regulation of splice isoforms. Cell Reports 44(10): 116412.
