Dear Osa friends,

I hope you are enjoying the beginning of this autumn season. I love the gentle reminder that the change in colors and the falling of leaves offers us to shed what we no longer need and to shore up for the inner remodeling of the winter season.

In this spirit, I want to share with you an interesting discussion this week about mitochondria. In the functional medicine world, we love to talk about these intracellular organelles because their quality and function has an outsized impact on our health and longevity. I’d like to introduce you to the concept of uncoupling in mitochondria and how this process of reducing mitochondrial efficiency can positively impact metabolic health.

Mitochondria are the sites of energy production in the cell. In addition to this crucial role, mitochondria also are involved in diverse functions including calcium buffering, programmed cellular death, heme synthesis, and steroid hormone synthesis. However, today we are focusing on energy production.

To begin, let’s briefly review the process of energy production

The creation of energy from food or stored energy is a process known as oxidative phosphorylation, which occurs inside cells in the inner membrane of the double-membraned mitochondria.

For cells to make usable energy, electrons are passed down a chain of carriers embedded in the inner mitochondrial membrane called the “electron transport chain” (ETC). This process releases energy which is used to pump hydrogen ions into an intermembrane space, thereby creating an electrochemical gradient. At the end of the ETC, this gradient is used to drive production of the body’s energy currency, adenosine triphosphate (ATP), by allowing the hydrogen ions to flow through a protein called ATP synthase. This reaction uses oxygen (hello, breathing!) and produces water. The body uses this newly produced energy to move, repair, and do the myriad of things it needs to do to stay alive. All good!

Electron leaking

However, in the process of passing electrons down the chain, some of these inevitably “leak” out. These loose electrons bind with oxygen and create superoxide radicals, which are a type of “reactive oxygen species” (ROS). At low levels, these molecules serve as signals which promote an increase in cellular antioxidant defenses, thereby neutralizing them. Still all good!

But, when production of ROS exceeds the body’s antioxidant capacity to neutralize them, these reactive molecules can bind to and damage DNA, lipids, and proteins– this is called “oxidative stress,” and it is associated with many degenerative conditions including the heavy hitters: cancer, cardiovascular disease, and neurodegenerative diseases like Parkinson’s and Alzheimer’s.

So, here’s the cool thing: our bodies have various ways of protecting against oxidative stress. One of the better studied of these is the “uncoupling” of electron transport from ATP production. This is accomplished by “uncoupling proteins” (UCPs), which allow hydrogen ions to flow back into the mitochondrial matrix through alternative paths that do not produce ATP and instead dissipate the energy as heat (this is called thermogenesis). This can be a protective mechanism because it not only reduces the production of reactive oxygen species that comes with ATP production but also protects against excessive ATP, which itself can also be harmful to the body.

Many studies, albeit mostly in rodents, have pointed to omega-3 fatty acids and mild calorie restriction as two factors which can influence the presence and activity of uncoupling proteins¹`²`³ . In humans, cold exposure has been found to induce thermogenesis via increase mitochondrial uncoupling in skeletal muscle⁴. For today, we’re going to discuss the potential of omega-3 fatty acids to positively influence mitochondrial health and energy balance in the body.

Mitochondrial uncoupling and omega-3 fatty acids: research studies

An interesting 2012 study in rats found that feeding with donkey milk (high omega-3), as compared to cow milk (low in omega-3 fats) or a control diet of lower fat content, led to increased energy dissipation through uncoupling proteins, reduced inflammatory markers, increased antioxidant enzyme activity, and improved ability to burn fat (which we call “beta oxidation”)¹. 

A more recent study published in 2019 found that a high fat diet enriched with omega-3 fatty acids protected mice from obesity and insulin resistance by increasing energy expenditure by an undetermined mechanism².  One group of these mice were bred to be deficient in uncoupling protein 1 (UCP1), which is one of the major UCPs studied, and the omega-3 fats had a similar effect in these mice as in mice without this deficit.  It is possible other UCPs were involved, or other mechanims of energy dissipation were employed by the cells as a result of the presence of omega-3 fats in the cellular membranes.

Human studies are limited regarding lifestyle and dietary influences on UCPs, but some muscle-centric studies have been conducted in because of the interest in UCP3, which has been found to be uniquely active in muscle cells.  For example, in a small group of soccer/”football” players, DHA supplementation of 1.14 grams per day further increased the expression of UCP3, which was also found to be enhanced by an 8-week exercise training regime⁵.

Omega-3s and metabolic dysfunction

Although studies examining effects of omega-3 fatty acids specifically on UCPs in people with metabolic disease are lacking, there is a good amount of research supporting the use of omega-3 fatty acids in fatty liver disease, which is a very serious chronic condition closely linked to the metabolic dysfunction of insulin resistance and type 2 diabetes.  (Fatty liver disease currently goes by two different names: metabolic dysfunction associated steatotic liver disease (MASLD) or nonalcoholic fatty liver disease,( NAFLD)). 

For example, a 2022 randomized placebo-controlled trial involving people with metabolic syndrome and NAFLD found that 3.6 grams per day of omega-3 fatty acid supplementation over a 12-month period significantly reduced liver fat and decreased the levels of a marker of liver disease called gamma-glutamyltransferase (GGT)⁶.  Likewise, a 2021 randomized placebo-controlled trial involved people with diabetes and NAFLD found that supplementation with 2 grams per day of omega-3 fatty acids significantly improved fatty liver, as measured by fatty liver index, lipid accumulation, and visceral adiposity index scores⁷. 

In theses studies, did omega-3 fats help decrease liver fat via increased energy expenditure involving UCPs and improved fat oxidation?  We cannot say with certainty, but it is promising to see that omega-3 supplementation alone can exert very beneficial effects in the face of severe metabolic dysfunction. (Imagine what can be done with personalized, multi-faceted diet and lifestyle interventions!)

Practical applications

Most of us could use more omega-3 fatty acids in our lives.    Along with omega-6 fatty acids, these types of fats are called “essential” because they cannot be produced by the body and must be consumed through the diet.  Sources of omega-3 fatty acids include walnuts, chia seeds, flax seeds, seaweed, algae, and fatty cold water fish such as salmon, herring, mackerel, sardines, and anchovies. 

It is important to know that the omega-3 fats contained in the listed nuts and seeds differ from those found in marine sources like algae and fish.  The difference is that the omega-3 fat in nuts and seeds is alpha-linolenic acid, a shorter-chain fat which, while still a beneficial component of cell membranes, must be converted in the cell membranes to create the longer chain length omega-3 fats which are known to be more biologically active, and this conversion rate is typically very low.  These longer chain length omega-3 fats are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and are found naturally occuring in marine sources.  For this reason, many people choose to supplement with DHA and EPA, from fish or algae sources.* 

A final note: Bringing inefficiency home

Uncoupling proteins are often classified among other biological processes that are termed “futile,” because they dissipate rather than create energy. in the literature, proton “leakage” via uncoupling proteins is described as an “inefficiency” of mitochondria. And yet, negative connotations notwithstanding, a growing body of research shows us that uncoupling proteins clearly have a role to play in our health.

This idea of beneficial inefficiency gets me wondering about the ways in which we might negatively classify ourselves as “inefficient,” or our efforts as “futile.” (I have so much to do today, and oh, if I could just do a little more! If only I didn’t need to sleep…If only there were more hours in the day! I just don’t get enough DONE.) When productivity is valued above all else, judging ourselves by our output can become second nature, and feeling inefficient or futile comes with the territory.

But consider how your mitochondria’s “inefficiencies” are life-giving and health-enhancing. It’s actually unhealthy to use all the energy you take in on productivity alone!

What kind of inefficiencies might you be able to enchance your life with this season? Creative outlets like reading, writing, or art. Connecting with friends in person. Taking time to prepare yourself or your family a meal, the nice and slow way. Taking time to move outside and appreciate the changing seasons. These are just a few examples that spring to mind. I’d love to hear how you are welcoming inefficiency to feed your mind and body this fall.

*Disclaimer: This does not constitute medical advice and is for general informational purposes only.  Please consult your healthcare provider to determine whether diet or supplement changes are right for you.

References

1. Lionetti, L., Cavaliere, G., Bergamo, P., Trinchese, G., De Filippo, C., Gifuni, G., Gaita, M., Pignalosa, A., Donizzetti, I., Putti, R., Di Palo, R., Barletta, A., & Mollica, M. P. (2012). Diet supplementation with donkey milk upregulates liver mitochondrial uncoupling, reduces energy efficiency and improves antioxidant and antiinflammatory defences in rats. Molecular nutrition & food research, 56(10), 1596–1600. ​https://doi.org/10.1002/mnfr.201200160​​https://pubmed.ncbi.nlm.nih.gov/22930490/​ (Article is unfortunately not open access. Please email me if you would like a copy of the full text.)
2. Oliveira, T. E., Castro, É., Belchior, T., Andrade, M. L., Chaves-Filho, A. B., Peixoto, A. S., Moreno, M. F., Ortiz-Silva, M., Moreira, R. J., Inague, A., Yoshinaga, M. Y., Miyamoto, S., Moustaid-Moussa, N., & Festuccia, W. T. (2019). Fish Oil Protects Wild Type and Uncoupling Protein 1-Deficient Mice from Obesity and Glucose Intolerance by Increasing Energy Expenditure. Molecular nutrition & food research, 63(7), e1800813. ​https://doi.org/10.1002/mnfr.201800813​ ​https://pubmed.ncbi.nlm.nih.gov/30632684/​
3. Green, C. L., Mitchell, S. E., Derous, D., Wang, Y., Chen, L., Han, J. J., Promislow, D. E. L., Lusseau, D., Douglas, A., & Speakman, J. R. (2020). The Effects of Graded Levels of Calorie Restriction: XIV. Global Metabolomics Screen Reveals Brown Adipose Tissue Changes in Amino Acids, Catecholamines, and Antioxidants After Short-Term Restriction in C57BL/6 Mice. The journals of gerontology. Series A, Biological sciences and medical sciences, 75(2), 218–229. ​https://doi.org/10.1093/gerona/glz023​ ​https://pubmed.ncbi.nlm.nih.gov/31220223/​
4. Wijers, S. L., Schrauwen, P., Saris, W. H., & van Marken Lichtenbelt, W. D. (2008). Human skeletal muscle mitochondrial uncoupling is associated with cold induced adaptive thermogenesis. PloS one, 3(3), e1777. ​https://doi.org/10.1371/journal.pone.0001777​ ​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258415/
5. Busquets-Cortés, C., Capó, X., Martorell, M., Tur, J. A., Sureda, A., & Pons, A. (2016). Training Enhances Immune Cells Mitochondrial Biosynthesis, Fission, Fusion, and Their Antioxidant Capabilities Synergistically with Dietary Docosahexaenoic Supplementation. Oxidative medicine and cellular longevity, 2016, 8950384. https://doi.org/10.1155/2016/8950384
6. Šmíd, V., Dvořák, K., Šedivý, P., Kosek, V., Leníček, M., Dezortová, M., Hajšlová, J., Hájek, M., Vítek, L., Bechyňská, K., & Brůha, R. (2022). Effect of Omega-3 Polyunsaturated Fatty Acids on Lipid Metabolism in Patients With Metabolic Syndrome and NAFLD. Hepatology communications, 6(6), 1336–1349. https://doi.org/10.1002/hep4.1906 https://pubmed.ncbi.nlm.nih.gov/35147302/
7. Sangouni, A. A., Orang, Z., & Mozaffari-Khosravi, H. (2021). Effect of omega-3 supplementation on fatty liver and visceral adiposity indices in diabetic patients with non-alcoholic fatty liver disease: A randomized controlled trial. Clinical nutrition ESPEN, 44, 130–135. https://doi.org/10.1016/j.clnesp.2021.06.015 https://pubmed.ncbi.nlm.nih.gov/34330456/

Photo credit: Nguyen Linh, from Unsplash