It seems that in life, everything looks like a biphasic curve. Train hard, and you will get fitter and strengthen your muscles. Train too hard, and you will be in trouble; it’s called “overtraining.”
We recognize tiredness and fatigue but don’t know how it works. Fatigue is often described by patients as a lack of energy, mental or physical tiredness, diminished endurance, and prolonged recovery after physical activity. The mechanisms underlying persistent fatigue are not well understood; however, mitochondrial disease causes fatigue, making mitochondrial dysfunction the likely biological mechanism for fatigue.
The primary source of fatigue and tiredness is that mitochondria, the engines that provide energy to the cells, are under stress. Mitochondria are organelles present in every body cell and produce about 90% of the body’s total energy. Mitochondrial respiration produces the energy-carrier adenosine triphosphate (ATP), which drives all the necessary chemical reactions in the body. Cells only contain a small, steady-state concentration of ATP molecules in cells which needs to be constantly re-generated because of energy demands. This is done by oxidative phosphorylation (in the mitochondria) or by glycolysis (in the cytosol). Maximal mitochondrial respiration increases with stress, and there can be up to a 100-fold increase in ATP consumption during vigorous activity compared with sleep. Mitochondria also participate in many other cellular actions, including redox signaling and cell danger responses.
The remarkable plasticity of mitochondria allows them to adjust their volume, structure, and capacity under conditions such as exercise, which is useful for improving metabolic health in individuals with various diseases or advancing age.
Mitochondria are complex organelles, and many different locations, molecules, and steps may be affected by mitochondrial dysfunction. If we could do magic, we could “fix” those steps and fix the fatigue that comes with old age and illness. Unfortunately, this is not possible yet, although there are some hints that manipulation may be possible in the future. Carnitine, Coenzyme Q10, the electron transport chain, and membrane composition and transport have been studied in healthy and ill individuals, but the conclusions varied with the study. Genetics plays a role (it always does), and immune response, viral infection, and the central nervous system also affect mitochondrial function. Conversely, because of the high energy requirement, neuronal functionality and viability largely depend on mitochondrial functionality: despite only weighing 2% of total body mass, the brain consumes 20% of oxygen and 50% of glucose supplied through delivery from the vasculature and is used to drive aerobic respiration within mitochondria.
Many factors regulate mitochondrial function, including cytokines, chaperones, chemokines, neurosteroids, and ubiquitins. The neurotransmitter serotonin increases the generation of new mitochondria–a process called mitochondrial biogenesis–in neurons, accompanied by an increase in cellular respiration and ATP, the cell’s energy currency. Serotonin reduces toxic reactive oxygen species in neurons, boosts anti-oxidant enzymes, and buffers neurons from the damaging effects of cellular stress.
New research shows that physical tiredness and what happens after “mental” work have a lot in common. Both physical and mental effort apparently exhausts the brain’s executive control system, leading to the reduced response of the brain’s lateral prefrontal cortex. This effect pushes us to reach for immediate rewards in decision-making (in other words, don’t go shopping when you are tired).
What can you do?
There is a lot of evidence that exercise and other activities help to keep the brain healthy. It’s important that we recognize that there is more to anti-age strategies than medicines or supplements. What we do with our bodies is probably the most important determinant of health (good or bad). But some important molecules can help. For example, melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Melatonin helps to maintain the optimal mitochondrial membrane potential and preserves mitochondrial functions.
For you skin
The topical route is the fastest and most direct; much of what you apply to the skin will be absorbed. Skin Actives has several ingredients that can help mitochondrial function. Our specialty proteins include antioxidants that will help decrease oxidative stress. Look into resveratrol, an ingredient with multiple benefits, or melatonin. We have products that address mitochondrial function directly. And remember: don’t add oxidative stress to your skin by exposing it to UV or oxidants. We have enough stress (oxidative and others) without adding to it!
Other useful posts
Bateman, J. (2018). Special Issue on “ROS and mitochondria in nervous system function and disease. FEBS Letters, 592(5), 661–662. doi:10.1002/1873-3468.13008
Bhat AH, Dar KB, Anees S, Zargar MA, Masood A, Sofi MA, Ganie SA. Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed Pharmacother. 2015 Aug;74:101-10. doi: 10.1016/j.biopha.2015.07.025. Epub 2015 Aug 7. PMID: 26349970.
Halson, S., Martin, D.T., Gardner, A.S., Fallon, K., and Gulbin, J. (2006). Persistent fatigue in a female sprint cyclist after a talent-transfer initiative. Int. J. Sports Physiol. Perform. 1, 65–69.
Blain, B., Hollard, G., and Pessiglione, M. (2016). Neural mechanisms underlying the impact of daylong cognitive work on economic decisions. Proc. Natl. Acad. Sci. USA 113:
Carelli, V., & Chan, D. C. (2014). Mitochondrial DNA: Impacting Central and Peripheral Nervous Systems. Neuron, 84(6), 1126–1142. doi:10.1016/j.neuron.2014.11.022
Fanibunda, S. E., Deb, S., Maniyadath, B., Tiwari, P., Ghai, U., Gupta, S., … Vaidya, V. A. (2019). Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis. Proceedings of the National Academy of Sciences, 201821332. doi:10.1073/pnas.1821332116
Filler, K., Lyon, D., Bennett, J., McCain, N., Elswick, R., Lukkahatai, N., & Saligan, L. N. (2014). Association of mitochondrial dysfunction and fatigue: A review of the literature. BBA Clinical, 1, 12–23. doi:10.1016/j.bbacli.2014.04.001 10.1016/j.bbacli.2014.04.001
Memme, J. M., Erlich, A. T., Phukan, G., & Hood, D. A. (2019). Exercise and mitochondrial health. The Journal of Physiology. doi:10.1113/jp278853
Meng-Yu Lei, Lin Cong, Zhi-Qi Liu, Zhuo-Fan Liu, Zhuo Ma, Kuan Liu, Jing Li, Yu Deng, Wei Liu, Bin Xu (2021) Resveratrol reduces DRP1‐mediated mitochondrial dysfunction via the SIRT1‐PGC1α signaling pathway in manganese‐induced nerve damage in mice, Environmental Toxicology, 37:282-298. https://doi.org/10.1002/tox.23397