Mitochondria are known as the powerhouses of eukaryotic cells. They are vital to our survival as they generate energy in the form of ATP from the food we eat. This process is known as cellular respiration. In addition, mitochondria store calcium for cell signaling activities, generate heat, and mediate cell growth and death (apoptosis). [efn_note] https://en.wikipedia.org/wiki/Mitochondrion[/efn_note]
When mitochondria stop functioning (mitochondrial dysfunction), the cells are starved of energy. So, depending on the type of cell, symptoms can vary widely. As a general rule, cells that need the largest amounts of energy, such as heart muscle cells and nerves, are affected the most by faulty mitochondria. Mitochondrial dna dysfunction is an important component of different diseases associated with aging, such as Type 2 diabetes [efn_note] Lowell. B.B, Shulman, G.I. “Mitochondrial dysfunction and type 2 diabetes.” Science. 2005 Jan 21;307(5708):384-7. [/efn_note] [efn_note] Parish, Rebecca, and Kitt Falk Petersen. “Mitochondrial dysfunction and type 2 diabetes.” Current diabetes reports vol. 5,3 (2005): 177-83. doi:10.1007/s11892-005-0006-3 [/efn_note] [efn_note] Pinti, M.V., et al. “Mitochondrial dysfunction in type 2 diabetes mellitus: an organ-based analysis.” Am J Physiol Endocrinol Metab. 2019 Feb 1;316(2):E268-E285. doi: 10.1152/ajpendo.00314.2018.[/efn_note] and Alzheimer’s disease [efn_note] Onyango, Isaac G et al. “Mitochondrial Dysfunction in Alzheimer’s Disease and the Rationale for Bioenergetics Based Therapies.” Aging and disease vol. 7,2 201-14. 15 Mar. 2016, doi:10.14336/AD.2015.1007 [/efn_note] [efn_note] Perez, Ortiz J.M et al. “Mitochondrial dysfunction in Alzheimer’s disease: Role in pathogenesis and novel therapeutic opportunities.” Br J Pharmacol. 2019 Sep;176(18):3489-3507. doi: 10.1111/bph.14585.[/efn_note]. It plays a significant role in chronic fatigue syndrome (C.F.S.), [efn_note] Myhill, Sarah et al. “Chronic fatigue syndrome and mitochondrial dysfunction.” International journal of clinical and experimental medicine vol. 2,1 (2009): 1-16.[/efn_note] [efn_note] Filler, Kristin et al. “Association of Mitochondrial Dysfunction and Fatigue: A Review of the Literature.” BBA clinical vol. 1 (2014): 12-23. doi:10.1016/j.bbacli.2014.04.001 [/efn_note] autism, [efn_note] Keren K. Griffiths and Richard J. Levy, “Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic-Based Associations, and Non-Energy-Related Mechanisms,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 4314025, 12 pages, 2017. https://doi.org/10.1155/2017/4314025. [/efn_note] [efn_note] Giulivi, Cecilia et al. “Mitochondrial dysfunction in autism.” JAMA vol. 304,21 (2010): 2389-96. doi:10.1001/jama.2010.1706 [/efn_note] [efn_note] Siddiqui, Maheen F et al. “Mitochondrial Dysfunction in Autism Spectrum Disorders.” Autism-open access vol. 6,5 (2016): 1000190. doi:10.4172/2165-7890.1000190[/efn_note]schizophrenia[efn_note] Monpays, C., et al. “Mitochondrial Dysfunction in Schizophrenia: Determination of Mitochondrial Respiratory Activity in a Two-Hit Mouse Model.” J Mol Neurosci. 2016 Aug;59(4):440-51. doi: 10.1007/s12031-016-0746-3. [/efn_note] [efn_note] Rajasekaran, A., et al. “Mitochondrial dysfunction in schizophrenia: pathways, mechanisms and implications.” Neurosci Biobehav Rev. 2015 Jan;48:10-21. doi: 10.1016/j.neubiorev.2014.11.005. Epub 2014 Nov 15. [/efn_note] and bipolar disorder. [efn_note] Clay, Hayley B et al. “Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia.” International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience vol. 29,3 (2011): 311-24. doi:10.1016/j.ijdevneu.2010.08.007 [/efn_note] [efn_note] Young, L Trevor. “Is bipolar disorder a mitochondrial disease?.” Journal of psychiatry & neuroscience : JPN vol. 32,3 (2007): 160-1. [/efn_note]
Description Of Mitochondria
Mitochondria are small, bean-shaped organelles that are difficult to see under a microscope unless they are stained. Unlike most other organelles, they have two membranes, an outer membrane layer that covers the organelle and contains it like a skin, and an inner membrane. The inner membrane is folded into cristae, which increases the surface area available for chemical reactions to take place. The fluid contained in the center of the mitochondria is called the mitochondrial matrix. The matrix includes the D.N.A. of the mitochondrial genome and the enzymes of the tricarboxylic acid (T.C.A.) cycle (also known as the citric acid cycle, or Krebs cycle), which metabolizes nutrients into by-products the mitochondrion can use for energy production.
Although they appear to be oval-shaped, the structure of mitochondria is continuously changing as a result of mitochondrial fission (breaking apart), mitochondrial morphology, and fusion (coming together) activity. This makes it quite difficult to count the mitochondria in a cell at any given time.
How Many are There in a Cell?
The number of mitochondria in a cell varies widely by cell type. For example, mature red blood cells have no mitochondria, whereas liver cells can have more than 2,000. Cells with a high demand for energy tend to have more significant numbers of mitochondria. For example, around 40 percent of the cytoplasm in heart muscle cells is taken up by mitochondria. [efn_note] Newman, T. “What are mitochondria?” Medical News Today. 2018 Feb 8. [/efn_note]
The amount of mitochondria in any given cell is continuously in flux. Cells that are actively growing, producing enormous amounts of some products such as digestive enzymes, actively transporting materials into the cell, or undergoing movement may display increased numbers of mitochondria during periods of activity and reduced numbers during periods of quiescence.
How Big Are Mitochondria?
Mitochondrial shapes consist of ovoid bodies having a diameter between 0.5 and 1.0 µm and a length of up to 7 µm. Usually, the lower the numbers of mitochondria per cell, the larger are the individual organelles. Inside the cell, mitochondria resemble the long balloons used to create balloon animals. If the mitochondria are too long, they can get tangled. In general, damaged mitochondria are fragmented, round, and swollen, [efn_note] Chang DTW, Reynolds IJ. Mitochondrial trafficking and morphology in healthy and injured neurons. Progress in Neurobiology. 2006;80:241–68. [/efn_note] [efn_note] Berman SB, Pineda FJ, Hardwick JM. Mitochondrial fission and fusion dynamics: the long and short of it. Cell Death and Differentiation. 2008;15:1147–52. [/efn_note] and such changes in mitochondria protein are observed in Parkinson’s disease. [efn_note] Perier C, Vila M. Mitochondrial biology and Parkinson’s disease. Cold Spring Harbor Perspectives in Medicine. 2012;4:a009332. [/efn_note] [efn_note] Dawson TM, Ko HS, Dawson VL. Genetic animal models of Parkinson’s disease. Neuron. 2010;66:646–61. [/efn_note] [efn_note] Botella JA, Bayersdorfer F, Gmeiner F, Schneuwly S. Modelling Parkinson’s disease in Drosophila. NeuroMolecular Medicine. 2011;11:268–80. [/efn_note] [efn_note] Wiemerslage, Lyle, and Daewoo Lee. “Quantification of mitochondrial morphology in neurites of dopaminergic neurons using multiple parameters.” Journal of neuroscience methods vol. 262 (2016): 56-65. doi:10.1016/j.jneumeth.2016.01.008 [/efn_note]
How Are Mitochondrial Sizes Regulated?
The mitochondrial network consists of highly dynamic cellular organelles, with the ability to change size, shape, and position over a few seconds. Many of these changes are due to the complex and co-ordinated processes of mitochondrial fission (a division of a single organelle into two or more independent structures) and fusion (the opposing reaction), which occur synchronously and continually in many cells of the body. It is the balance between these two processes that determine the overall structure of mitochondria in any given cell. [efn_note] Scott, Iain, and Richard J Youle. “Mitochondrial fission and fusion.” Essays in biochemistry vol. 47 (2010): 85-98. doi:10.1042/bse0470085 [/efn_note]Keeping mitochondria at optimal sizes is essential for cellular health and longevity.
Mitochondrial fusion is critical for the maintenance of mitochondrial function. It allows the spreading of mitochondrial D.N.A. throughout the mitochondrial compartment, which optimizes mitochondrial function and prevents the accumulation of mitochondrial mutations during aging. Further, it acts as a “rescue” mechanism that prevents the elimination of damaged mitochondria by mitophagy. [efn_note] Twig G., Shirihai O.S. The interplay between mitochondrial dynamics and mitophagy. Antioxid. Redox Signal. 2011;14:1939–1951. doi: 10.1089/ars.2010.3779. [/efn_note] A blockage of mitochondrial fusion results in a loss of mitochondrial membrane potential. [efn_note] Chen H., Detmer S.A., Ewald A.J., Griffin E.E., Fraser S.E., Chan D.C. Mitofusins mfn1 and MFN2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J. Cell Biol. 2003;160:189–200. doi: 10.1083/jcb.200211046. [/efn_note]
Mitochondrial fission, on the other hand, plays an essential role in mitochondrial replication and the removal of damaged organelles by selective autophagy. [efn_note] Suárez-Rivero, Juan M et al. “Mitochondrial Dynamics in Mitochondrial Diseases.” Diseases (Basel, Switzerland) vol. 5,1 1. 23 Dec. 2016, doi:10.3390/diseases5010001[/efn_note]
In the absence of mitochondrial fission, ongoing fusion causes the formation of mitochondrial nets with few tubular ends. [efn_note] Bleazard, W., J.M. McCaffery, E.J. King, S. Bale, A. Mozdy, Q. Tieu, J. Nunnari, and J.M. Shaw. 1999. The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast. Nat Cell Biol. 1:298–304. [/efn_note] [efn_note] Sesaki, H., and R.E. Jensen. 1999. Division versus fusion: Dnm1p and Fzo1p antagonistically regulate mitochondrial shape. J Cell Biol. 147:699–706. [/efn_note] [efn_note] Smirnova, E., D.L. Shurland, S.N. Ryazantsev, and A.M. van der Bliek. 1998. A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol. 143:351–8.[/efn_note] This may occur as a result of insufficient amounts of the regulating protein, known as dynamin-related protein 1 (Drp1), which causes the mitochondria to get too long and tangled. Too much Drp1 results in excessive mitochondrial fission and too many short mitochondria. [efn_note]Frank, S., B. Gaume, E.S. Bergmann-Leitner, W.W. Leitner, E.G. Robert, F. Catez, C.L. Smith, and R.J. Youle. 2001. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell. 1:515–25 [/efn_note] Both scenarios result in mitochondrial dysfunction, which given the critical functions of mitochondria in cell homeostasis, can cause a great variety of diseases which can affect almost all the tissues and organs in the body [efn_note] Lin M.T., Beal M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;443:787–795. doi: 10.1038/nature05292.[/efn_note]. This includes neurodevelopmental disorders or neurodegenerative diseases, such as Alzheimer’s or Parkinson’s. [efn_note]Michelle W. Lee, et al., “Molecular Motor Dnm1 Synergistically Induces Membrane Curvature To Facilitate Mitochondrial Fission,” ACS Cent. Sci., 2017, 3 (11), pp 1156–1167; DOI: 10.1021/acscentsci.7b00338 [/efn_note]
Fission and fusion interact to create a diversity of mitochondrial structures. The arrangements generated include rods of various lengths, sausage string appearance, looped structures, and multiple branched and network arrangements. [efn_note] McCarron, John G et al. “From structure to function: mitochondrial morphology, motion and shaping in vascular smooth muscle.” Journal of vascular research vol. 50,5 (2013): 357-71. doi:10.1159/000353883 [/efn_note] The numerous shapes are related to the function of the cells.
How You Can Take Care of Your Mitochondria
The mitochondria are the powerhouses of the mammalian cell and critical for life. However, they are susceptible to nutrient deficiencies, environmental toxins, and oxidative damage, so special care must be taken to protect and nourish them. To work efficiently, mitochondria need to be resilient. Resilience is built through the action and stimulation of mitochondria by hormetic stressors (a mild stressor that helps build resistance to other stressors), including exercise, calorie restriction, extreme cold and heat exposure, red and near-infrared red light exposure, hypoxia, U.V. light, Xenobiotics (like caffeine, nicotine, alcohol and other drugs) as well as dietary phytonutrients.
Diet & Intermittent Fasting
A diet rich in a variety of plant phytonutrients provides the essential micronutrients the body needs for energy production as well as acting as an antioxidant and hormetic stressor responsible for reducing inflammation and initiating mitochondrial growth and biogenesis (the creation of new individual mitochondria). Plant phytonutrients include polyphenols such as:
- resveratrol in red grapes
- sulforaphane in broccoli
- curcumin in turmeric
- E.C.G.C. in green tea
- epicatechins in cacao
- ellagic acid in pomegranates
- carotenoids in tomatoes
- anthocyanins in berries
Although eating a healthy diet is critically important for mitochondrial health, when you eat and how you eat can also affect mitochondrial function. Calorie restriction and time-restricted feeding (TRF) (or intermittent fasting) have been shown to optimize mitochondrial function and extend lifespan.
The mild stress placed upon the body by not eating enough acts as a hormetic stressor and activates a wide variety of protective pathways within the body, ramping up anti-inflammatory and antioxidant defenses. Fasting for medical purposes has been suggested since the time of ancient Chinese, Greek, and Roman physicians [efn_note]Kastner M. Fasting. In: Kastner M, Burroughs H, editors. Alternative healing: The complete AZ guide to over 160 different alternative therapies. Las Mesa: Halcyon Publishing; 1993. pp. 92–93. [/efn_note]. Even Benjamin Franklin has been quoted as saying, “The best of all medicines is resting and fasting.” [efn_note] A Dictionary of Thoughts. Tyron Edwards; 1908. p. 339.[/efn_note]
Carb cycling is also a form of hormesis, and carbohydrate restriction produces ketone bodies, which may have many protective effects. Ketone bodies are an extremely energy-efficient source of fuel. They produce more ATP than glucose. Using ketone bodies for energy decreases the production of damaging free radicals and lowers inflammation [efn_note] Veech, RL. “The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism.” Prostaglandins Leukot Essent Fatty Acids. 2004 Mar;70(3):309-19. DOI: 10.1016/j.plefa.2003.09.007[/efn_note] [efn_note] Seyfried, T.N, Mukherjee, P. “Targeting energy metabolism in brain cancer: review and hypothesis.” Nutr Metab (Lond). 2005 Oct 21;2:30. DOI: 10.1186/1743-7075-2-30 [/efn_note], which can cause severe disease and damage. [efn_note] Haces, ML. et al. “Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions.” Exp Neurol. 2008 May;211(1):85-96. doi: 10.1016/j.expneurol.2007.12.029.[/efn_note] Ketogenesis improves mitochondrial health by activating the Nrf2 pathway and increasing mitochondrial biogenesis.
Exercise (Anaerobic Exercise)
Movement has a profound effect on neurotransmitters that regulate wakefulness. When you sit around a lot during the day, your body thinks it is time to rest and will start preparing for sleep. Sitting and inactivity can lead to a decrease in the number and health of mitochondria, thus slowing down metabolism over time. [efn_note]Timmons JA, et al. “Expression profiling following local muscle inactivity in humans provides new perspective on diabetes-related genes.” Genomics. 2006 Jan;87(1):165-72. [/efn_note] [efn_note] Ringholm S, et al. “Bed rest reduces metabolic protein content and abolishes exercise-induced mRNA responses in human skeletal muscle.” Am J Physiol Endocrinol Metab. 2011 Oct;301(4):E649-58. doi: 10.1152/ajpendo.00230.2011.[/efn_note] Exercise signals your body to wake up. Even small, simple actions such as taking short movement breaks and walking more will increase your N.E.A.T. (Non-Exercise Activity Thermogenesis) and keep you alert and energized. For well-trained individuals, including High-Intensity Interval Training (H.I.I.T.), especially in a fasted state, can improve energy levels.
Though eating a healthy, phytonutrient-rich diet, exercising regularly, and getting good quality sleep are vitally important for improving energy levels, it is often difficult to do while balancing the demands of life. This is where supplements can play an important role. Studies have shown that combinations of supplements can significantly reduce fatigue and other symptoms associated with mitochondrial damage and can naturally restore mitochondrial function. [efn_note] Nicolson, Garth L. “Mitochondrial Dysfunction and Chronic Disease: Treatment With Natural Supplements.” Integrative medicine (Encinitas, Calif.) vol. 13,4 (2014): 35-43.[/efn_note]
N.T. factors phospholipid complex and astaxanthin (a red pigment found in krill and other seafood) are supplements that support the mitochondrial membrane. They play a role in preventing damage to the mitochondrial membrane from oxygen radicals and replacing/repairing damaged membrane tissues. Lipid therapy has proved very effective at reducing fatigue. [efn_note]Nicolson GL. Metabolic syndrome and mitochondrial function: molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function. J Cell Biochem. 2007;100(6):1352–1369. [/efn_note] [efn_note] Nicolson GL, Settineri R. Lipid Replacement Therapy: a functional food approach with new formulations for reducing cellular oxidative damage, cancer-associated fatigue and the adverse effects of cancer therapy. Funct Foods Health Dis. 2011;1(4):135–160.[/efn_note] In one study, oral administration of N.T. Factor for 12 weeks resulted in a 35.5% reduction in tiredness and a 26.8% increase in mitochondrial function. [efn_note]Agadjanyan M, Vasilevko V, Ghochikyan A, et al. Nutritional supplement (NTFactor) restores mitochondrial function and reduces moderately severe fatigue in aged subjects. J Chronic Fatigue Syndr. 2003;11(3):23–26. [/efn_note]
Other supplements include cofactors in mitochondrial energy production, which assist with biological, chemical reactions in the body. These can be vitamins, minerals, or coenzymes that work synergistically with enzymes in the production of ATP (our energy currency) and include magnesium, coenzyme Q10, B vitamins, L-carnitine, creatine, and D-ribose.
Supplements that protect the mitochondria and activate mitochondrial biogenesis are also useful adjuncts to a healthy lifestyle. Amla (or Indian gooseberry), turmeric, alpha-lipoic acid (A.L.A.), and green tea are potent antioxidants that prevent/reduce oxidative damage and decrease inflammation in the mitochondria. Another supplement, PQQ, or pyrroloquinoline quinone, works synergistically with the master antioxidant glutathione (produced by the body) to support mitochondrial function [efn_note] Harris, C. B. et al. Dietary pyrroloquinoline quinone (PQQ) alters indicators of inflammation and mitochondrial-related metabolism in human subjects. J. Nutr. Biochem. 24, 2076–2084 (2013).[/efn_note] and activate mitochondrial biogenesis. [efn_note] Chowanadisai, W. et al. Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression. J. Biol. Chem. 285, 142–152 (2010). [/efn_note] [efn_note] Hwang, P. & Willoughby, D. S. Mechanisms Behind Pyrroloquinoline Quinone Supplementation on Skeletal Muscle Mitochondrial Biogenesis: Possible Synergistic Effects with Exercise. J. Am. Coll. Nutr. 1–11 (2018).[/efn_note]
The ability of cells to produce energy is directly related to the ability of mitochondria to (1) convert the energy from food to reduced nicotinamide adenine dinucleotide (NADH) and (2) transfer electrons from NADH to the electron transport chain and eventually produce ATP. However, the amount of N.A.D. in your body naturally falls with age [efn_note]Massudi, H. et al. “Age-associated changes in oxidative stress and NAD+ metabolism in human tissue.” PLoS One. 2012;7(7):e42357. doi: 10.1371/journal.pone.0042357. [/efn_note], which may impair biological functions important to health and contribute to age-related diseases. It’s believed that increasing N.A.D. through supplementation may improve symptoms and/or delay these conditions. Citrus bioflavonoids, resveratrol, quercetin, N-acetyl-cysteine (N.A.C.), and niacin or nicotinamide all act as precursors that boost levels of NAD+. [efn_note] Boesten, Daniëlle M P H J et al. “Protective Pleiotropic Effect of Flavonoids on NAD⁺ Levels in Endothelial Cells Exposed to High Glucose.” Oxidative medicine and cellular longevity vol. 2015 (2015): 894597. doi:10.1155/2015/894597 [/efn_note] [efn_note]Cuzzocrea, S. et al. “Protective effect of N-acetylcysteine on cellular energy depletion in a non-septic shock model induced by zymosan in the rat.” Shock. 1999 Feb;11(2):143-8. [/efn_note] [efn_note] Trammell, SA. et al. “Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.” Nat Commun. 2016 Oct 10;7:12948. doi: 10.1038/ncomms12948. [/efn_note] [efn_note]Martens, CR. et al. “Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults.” Nat Commun. 2018 Mar 29;9(1):1286. doi: 10.1038/s41467-018-03421-7[/efn_note]
For more information on these supplements and many others, please read the article titled “The Best Vitamins and Supplements to Fight Fatigue.”
Mitochondria generate most of the cell’s energy in the form of adenosine triphosphate (ATP) and are thus termed the powerhouse of the cell. Mitochondria are commonly between 0.75 and 3 μm² in the area but vary considerably in size and structure. Their numbers vary by the type and function of the cell they are situated in, and their size and shape are primarily determined by the delicate balance between mitochondrial fission and fusion events.
As mitochondria are so critical for health and energy production but are also susceptible to nutrient deficiencies and damage, we must protect and nourish them. This can be achieved by practicing good lifestyle habits (such as eating a healthy, phytonutrient-rich diet and exercising regularly) as well as limiting environmental toxins, intermittent fasting, and judiciously using supplements, as required.