Mitochondria have recently become a focus of attention among healthcare professionals, fitness trainers, nutritionists and whoever considers health and wellness seriously. Why is that? What do we know about mitochondria?

Mitochondria as the Powerhouses of the Cell

Mitochondria are often referred to as the powerhouses of the cell. They are tiny organelles in the cell and produce the majority of energy that the cell requires. The number of mitochondria per cell varies widely; for example, platelets in the blood contain only several mitochondria, whereas the number of mitochondria in muscles and the liver can exceed a thousand.

The Electron transport chain (ETC) or the respiratory chain is located in a fold of mitochondrial inner membrane. ETC consists of four large protein complexes (Complexes I – IV), pumps protons (H+) out into the intermembrane space through the transfer of electron, and generates the electrochemical gradient of protons across the inner membrane. ATP synthase (Complex V) utilizes this gradient-driven energy to convert ADP into a high energy compound, ATP (a process called as oxidative phosphorylation). Oxygen is the proton and electron acceptor and forms water at the end of the process. Watch a fascinating video – Electron Transport and ATP Production in Cells – by BioVisions at Harvard.

As we age, the integrity and functions of mitochondria decline. This leads to the increased production of mitochondrial reactive oxygen species and the accumulation of mutated mitochondrial DNA. This phenomenon constitutes the pillar of “mitochondrial free radical theory of aging”. However, there are more to be said for the role of mitochondria in the body.

Mitochondria as the Powerhouses of Immunity

In 2017, a group of scientists led by Dr. O’Neill published in prestigious Nature Immunology an article titled “Mitochondria are the Powerhouses of Immunity”. The group is a pioneer in immunometabolism (see the footnote) and studies the metabolic reprogramming of immune cells in health and disease.

Briefly, immune responses to infection and tissue injury are accompanied by changes in metabolism among immune cells – often the shift from oxidative phosphorylation to a less efficient form of energy production, glycolysis. Evidence suggests that, if the integrity and functions of mitochondria are compromised, the immune system begins to respond to infection and tissue injury erratically.

Improving the Immune System

According to Harvard Health Publishing (updated on 6th April 2020), we can improve our immune system by choosing healthy lifestyle, for example:

• Eat a balanced diet.
• Exercise regularly.
• Maintain healthy weight.
• Get adequate sleep.
• Minimize stress.

What is the basis of their advice? Obesity is implicated in metabolic diseases, such as high blood pressure, high cholesterol, type 2 diabetes, and fatty liver disease. Obesity-induced metabolic abnormality is also linked to allergy, asthma, autoimmune diseases, neurodegenerative diseases, and several types of cancer. The common feature of these diseases is the dysregulation of immune responses (seen as chronic low-grade inflammation). This has led to a realization that healthy lifestyle choices have positive metabolic consequences and therefore contribute to the improvement of the immune system. Importantly, we now know that mitochondria are at the nexus of the interaction between metabolic and immune processes.

To Immunologists:-

“Immunologists used to avoid metabolism, but that is no longer possible. Now that we must talk about it, how can we do so in a way that enhances and clarifies our understanding of the role metabolism plays in the immune response?” Murphy & O’Neill (2020)

Our Approach

We cannot emphasize enough how important healthy lifestyle choices are in keeping our immune system fit and resilient. However, we live in a fast-paced world and healthy lifestyle choices have become luxury. That is why we started exploring natural and perhaps holistic ways to improve our immune system.

Molecular hydrogen (H2) is one of our choices. Briefly, H2 is among common intestinal gases along with oxygen, nitrogen, carbon dioxide, and methane. Numerous studies over the past decade suggest that H2 has an antioxidant property. In addition, a group of scientists led by Dr. Ishibashi discovered that H2 could rectify the flow of electron along the mitochondrial electron transport chain and normalize the electrochemical potential between mitochondrial inner and outer membranes. Group’s discovery suggests that H2 can restore the cross-membrane transport of elements and compounds, which are critical in maintaining the integrity and functions of mitochondria – as the powerhouses of the cell and the immunity.

1. Ishibashi, T. 2019. Therapeutic efficacy of molecular hydrogen: A new mechanistic insight. Current Pharmaceutical Design, 25: 1-10.

2. Ishihara, G. et al., 2020. Molecular hydrogen suppresses superoxide generation in the mitochondrial complex I and reduced mitochondrial membrane potential. Biochemical and Biophysical Research Communication, 522: 965-970.

Immunometabolism

Nature Reviews Immunology, 30th April 2019

“Over the past decade, “immunometabolism” has become one of the most exciting areas of translational research. Metabolic processes regulate immune cell responses in healthy individuals as well as during infection, cancer, autoimmunity, and obesity. Moreover, immune responses are shaped not only by host metabolites, but also by metabolites derived from the microbiota and infectious agents. These discoveries are paving the way for novel therapies for chronic inflammatory and autoimmune diseases, as well representing a new class of cancer immunotherapies.”

Selected Articles 

1. Mathis, D. & Shoelson, S.E., 2011. Immunometabolism: an emerging frontier. Nature Reviews Immunology, 11: 81-83.
2. O’Neill, L.A.H. & Hardie, D.G., 2013. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature, 493: 346-355.
3. Oh, J. et al., 2014. Stem cell Aging: mechanisms, regulators and therapeutic opportunities. Nature Medicine, 20 870-880.
4. Finkel, T., 2015. The metabolic regulation of aging. Nature Medicine, 21: 1416-1423.
5. O’Neill, L.A.H. et al., 2016. A guide to immunometabolism for immunologists. Nature Reviews Immunology, 16: 553-565.
6. Buck, M.D. et al., 2017. Metabolic instruction of immunity. Cell, 169: 570-586.
7. Koelwyn, G.J. et al., 2017. Exercise-dependent regulation of the tumour microenvironment. Nature Reviews Cancer, 17: 620-632.
8. Mehta, M.M. et al., 2017. Mitochondrial control of immunity: beyond ATP. Nature Reviews Immunology, 17: 608-620.
9. Mills, E.L. et al., 2017. Mitochondria are the powerhouses of immunity. Nature Immunology, 18: 488-498.
10. Bantug, G.R. et al., 2018. The spectrum of T cell metabolism in health and disease. Nature Reviews Immunology, 18: 19-34.
11. Zhong, Z. et al., 2018. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature, 560: 198-203.
12. Khacho, M. et al., 2019. Mitochondria as central regulators of neural stem cell fate and cognitive function. Nature Reviews Neuroscience, 20: 34-48.
13. Ryan, D.G. et al., 2019. Coupling Krebs cycle metabolites to signalling in immunity and cancer. Nature Metabolism, 1: 16-33.
14. Chapman, N.M. et al., 2020. Metabolic coordination of T cell quiescence and activation. Nature Reviews Immunology, 20: 55-70.
15. Murphy, M.P. & O’Neill, L.A.H., 2020. How should we talk about metabolism? Nature Immunology, In Press.