In a laboratory led by Dr. Tal Yardeni from Sheba Medical Center and supported by a five-year grant from the National Science Foundation, the question is being examined whether natural variants in mitochondrial DNA affect the activity of immune cells and the interactions between them – through metabolites, epigenetics, and the response to inflammation, infection, or cancer.
“We are used to thinking of mitochondria as the powerhouse of the cell. But for us, they are also a communication system.” This is how Dr. Tal Yardeni, head of the Mitochondrial Research Laboratory at Sheba Medical Center, describes the starting point of her research: Can small and “normal” differences in mitochondrial DNA (mtDNA) change the way immune system cells function – and especially the interactions between them – and thus affect disease risk and response to treatments. This is also the core formulation of the research question at the center of a five-year research grant from the National Science Foundation.
Why mtDNA?
Every cell has two “instructions.” One is the nuclear DNA, which comes from both parents. The other is found in the mitochondria, and is passed only through the mother. The mtDNA is much shorter, structured as a circle, and similar in characteristics to the DNA of bacteria – a hint at the famous evolutionary story according to which mitochondria began as a bacterium that lived in association with an ancient cell. Most cells have hundreds to thousands of mitochondria, and therefore also a large number of mtDNA copies.
What is the question? What is the role of mitochondrial DNA in the activity of immune system cells and the interactions between them?
For many years, mitochondria were primarily considered an “energy factory.” Today, it is clear that they also participate in stress control, signaling inside and outside the cell, and are closely linked to the nucleus. In Dr. Yardeni’s lab, which focuses on the intersection of mitochondria, immunology, and metabolism, the question is not only what happens when mitochondria “break down” in rare diseases, but also what the meaning of natural genetic variation in mtDNA is – variation that has been created throughout evolution and accumulated in ancestral groups (haplotypes). According to results from the lab, such variants may affect immune cell states, response to treatment, and disease risk.
What exactly are they testing in the immune cells?
The main focus is to identify which changes in mtDNA affect mitochondrial function. Even “normal” variants, which are not mutations that cause dysfunction, can alter mitochondrial activity – and significantly skew the cell’s activity and immune function.
how does it happen?
Mitochondria produce metabolites – chemical products of metabolic processes. Some of these metabolites serve as auxiliary substances that regulate epigenetics in the nucleus, that is, the “control buttons” that determine which genes will be activated and with what intensity. When the amounts change, the patterns of epigenetic marking can also change, and subsequently the expression of the genes that determine the function of the cell. At the end of the chain, an immune cell is obtained that behaves differently: it can be more “pro-inflammatory”, or, conversely, more restrained.
In order not to remain at the level of hypothesis, Dr. Yardeni and her team use unique mouse models in which it is possible, in fact, to separate the mtDNA from the nuclear background. That is, to create a situation in which two mice are “identical” in the nuclear DNA, but different in the mtDNA. This way, the hypotheses can be tested in a clean way: whether the difference in immune behavior stems from the mitochondria and not from hundreds of thousands of other differences in the genome.
Why mtDNA? Every cell has two “instructions books.” One is the nuclear DNA, which comes from both parents. The other is found in the mitochondria, and is passed down only through the mother.
What is actually being measured? Several layers at the same time:
- Mitochondrial activity (e.g. cellular respiration indices).
- Metabolite profile.
- Epigenetic profile (such as methylation and acetylation).
- Gene expression in different immune cells.
- Function of the cells of the immune system.
One of the interesting results that emerged from Dr. Yardeni's study is that differences between cells are not seen in a "resting state," but rather at the moment of activation: when responding to infection, under conditions of inflammation, or facing a cancerous tumor. In other words: mtDNA does not necessarily change the "identity" and differentiation of the cell in advance, but rather the way it responds when a quick decision needs to be made.
This is where the ISF question comes in. Beyond understanding how a T cell or innate immune cell functions on its own, it is also important to understand the interactions between them: how one cell can “turn on” or “turn off” another cell, what messages and signals pass between them, and how all of these dynamics change when the genetic makeup of the mitochondria (mtDNA) is different. In fact, many of the critical decisions of the immune system are made not within a single cell, but in the dialogue between cells. This is precisely why the official wording of the grant emphasizes not only the activity of the immune cells themselves, but also the interactions between them – where biology becomes a truly complex and influential system.
Why is this important in medicine?
If natural variation in mtDNA does indeed direct the pattern of immune response, it might help to understand why certain genetic groups have been linked in the literature to higher risk of, or protection from, certain diseases. One could also imagine careful, scaled applications of “personalized medicine”: not as a big headline, but as a tool that adds another layer of information about how the immune system might behave in a given individual.
Early on, the practical application could be simple: a biomarker that predicts response to treatment. Later, it might be possible to change the “state” of mitochondria in certain cells to bias an immune response—to increase cancer attack, or to reduce the risk of hyperinflammation and autoimmune diseases. This is not yet an immediate clinical goal, but that is precisely why grants like the one from the National Science Foundation are aimed at mechanistic questions: to understand the cause-and-effect chain all the way through, before trying to “tune” it.
More of the topic in Hayadan:
Written by Avi Blizovsky
