Mitochondria are found in every cell, except mature red blood cells and vary from 200 to 2000 depending cell function (muscle, liver and brain cells have higher levels). Mitochondria are actually bacterial in nature and likely arose from alphaproeobacteria ,which have their own DNA coding 13 polypeptides and also RNA.
These minute powerhouses are responsible for regulating and storing cellular energy. They convert ingested energy, for example glucose, into a format the body can actively use, called ATP (Adenosine Tri Phosphate).
ATP carries energy within its atomic bonds which can be released for use in biochemical processes. Hydrolysis of ATP to ADP (Adenosine Di Phosphate) liberates energy: breaking the phosphate bond is exothermic (it gives off energy) due to the inherent instability of ATP which would ‘prefer’ to be in its ADP state. After conversion of ATP to ADP, and release of the energy holding the phosphate in place, the ATP molecule (now ADP) is ‘spent’ and needs to be recycled.
Electrochemical reactions (collectively known as oxidative phosphorylation) take place inside the mitochondria along the electron transport chain to reattach a phosphate group to create ATP again. This endless recycling of ADP to ATP is needed to maintain energy production.
Even though each cell contains approximately one billion ATP molecules it is only sufficient to meet the cell’s energy requirements for a few minutes and constant activity is required to keep energy flowing – amazingly humans manufacture and consume their own weight in ATP every day.
Mitochondria have diverse functions including ATP production, biomolecule synthesis, ionic homeostasis and antioxidant defense. As cells age and accumulate damage, mitochondria less readily meet ATP demands, thereby diminishing the cells’ functions and regenerative capacity. After toxicant exposure or cell stress, mitochondria can be damaged, and increased free radical production may be followed by persistent mitochondrial dysfunction.
Role of mitochondria:
- Energy regulation
- Involved in the maintance of intracellular calcium levels and calcium buffering (required for cellular signaling)
- Regulate cell numbers and defend against unwanted or dangerous cells by triggering programmed cell death (apoptosis)
- Signaling between the human (nuclear) and mitochondrial genome is also controlled by the mitochondria themselves via the production of Reactive Oxygen Species (ROS)
- Mitochondrial biogenesis, fusion and fission have roles in aspects of immune cell activation
- Mitochondria are critical for signalling by three major innate immune pathways: RIG-I/MAVS, NLRP3 and TLR9
Causes of Mitochondrial Dysfunction:
Heavy metal toxicity such as lead, nickel, cadmium, mercury
Heavy metals have been reported to affect cellular organelles and components such as cell membrane, mitochondrial, lysosome, endoplasmic reticulum, nuclei, and some enzymes involved in metabolism, detoxification, and damage repair.
Kurochkin, I. O., Etzkorn, M., Buchwalter, D., Leamy, L., & Sokolova, I. M. (2011). Top-down control analysis of the cadmium effects on molluscan mitochondria and the mechanisms of cadmium-induced mitochondrial dysfunction. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 300(1), R21–R31. http://doi.org/10.1152/ajpregu.00279.2010
Environmental chemicals such as PCB, pesticides, diesel exhaust
Chemicals or environmental mitochondrial toxicities are known to interfere with mitochondrial function.
Responsible for these toxicities are:
- Cigarette smoke
- Air pollution and particulates
- Poly aromatice hydrocarbons (PAHs)
- Herbicides 2, 4-dichlorophenoxyacetic acide, dinoseb
- mtDNA geneotoxicants, mutagens
- and others
Schmidt, C. W. (2010). Unraveling environmental effects on mitochondria. Environ Health Perspect, 118(7), A292–A297. http://doi.org/10.1289/ehp.118-a292
Vaccine reactions
Thimerosal an ethylmercury releasing compound has been associated with cellular / mitochondrial damage, reduced oxidative–reduction activity, cellular degeneration, and cell death.
Geier, D. a., King, P. G., & Geier, M. R. (2009). Mitochondrial dysfunction, impaired oxidative-reduction activity, degeneration, and death in human neuronal and fetal cells induced by low-level exposure to thimerosal and other metal compounds. Toxicological & Environmental Chemistry, 91(4), 735–749. http://doi.org/10.1080/02772240802246458
Endogenous toxins from gut pathogens such as clostridia.
Clostridia spp. are producers of the short-chain fatty-acid propionic acid following the fermentation of dietary carbohydrates and some proteins. Propionic acid as well as other short-chain fatty-acid bacterial fermentation products can modulate cell signaling, cell interactions (e.g. gap junctions), gene expression, immune function and neurotransmitter synthesis and release as well as influence mitochondrial and lipid metabolism. Interestingly, propionic acid is also endogenously present or added as a food preservative to a wide variety of foods including refined wheat and dairy products.
Medications
Toxicity from pharmaceutical drugs is well documented causing mitochondrial disorders.
Aspirin, Acetaminophen, Salicylates, Indomethacin/Naproxen, Lidocaine, Tetracycline, Statins, Metformin, HIV medications, Amiodarone, Citalopram, Fluoxetine, Haloperidol, Alprazolam/Diazepam, Phenobarbital
Neustadt, J., & Pieczenik, S. R. (2008). Medication‐induced mitochondrial damage and disease. Molecular Nutrition & Food Research, 52(7), 780–788. http://doi.org/10.1002/mnfr.200700075
Poor Methylation
Decreased MTHFR activity due to MTHFR 677CT strings the methylation cycle, resulting in increasing levels of homocysteine, increased ROS production, decreased S-adenosylmethionine (SAM) production, and increased oxidative stress, which greatly increases the rate of glutathione (GSH) depletion.
Chronic oxidative stress and GSH depletion, gravely impact not only mitochondrial function, but every cell and system in the body.
Glutathione deficiency
Glutathione emerges as the main line of defense for the maintenance of the appropriate mitochondrial redox environment to avoid or repair oxidative modifications leading to mitochondrial dysfunction and cell death.
Jain, A., Mårtensson, J., Stole, E., Auld, P. A., & Meister, A. (1991). Glutathione deficiency leads to mitochondrial damage in brain. Proceedings of the National Academy of Sciences of the United States of America, 88(5), 1913–7. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2000395
Nutritional imbalances / deficiencies
Nutritional imbalances / deficiencies are leading to susceptibility for poor cellular function.
Infections
Any kind of chronic infections such as bacterial, yeast and virus (candida or Epstein Barr virus) can suppress mitochondrial function.
Vernon, S., Whistler, T., Cameron, B., Hickie, I., Reeves, W., & Lloyd, A. (2006). Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr Virus. BMC Infectious Diseases, 6(1), 15. http://doi.org/10.1186/1471-2334-6-15
Inflammation
Chronic inflammation has a direct impact on mitochondrial function.
Mills, E. L., Kelly, B., Logan, A., Frezza, C., Murphy, M. P., Neill, L. A. O., … Bryant, C. E. (2016). Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Article Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages, 457–470. https://doi.org/10.1016/j.cell.2016.08.064
Oxalate damage
Oxalates are highly reactive molecules; present in our body as crystals or crystalline structures with jagged edges. Oxalates affect mitochondrial function and can create inflammation; thus influencing every system in the body. Oxalates could be a hidden source of headaches, urinary pain, genital irritation, joint, muscle, intestinal or eye pain. Other common oxalate-caused symptoms may include mood conditions, anxiety, sleep problems, weakness, or burning feet. Indicators can be digestive, respiratory, or even bedwetting for children.
Veena, C. K., Josephine, A., Preetha, S. P., Rajesh, N. G., & Varalakshmi, P. (2008). Mitochondrial dysfunction in an animal model of hyperoxaluria: A prophylactic approach with fucoidan. European Journal of Pharmacology, 579(1-3), 330–336. http://doi.org/10.1016/j.ejphar.2007.09.044
Mitochondrial Regulation and Protection
There are three major cell nutritional sensors, mTOR, AMPK and Sirtuins, which are involved in regulation of mitochondrial physiology.
They control mitochondrial biogenesis, dynamics (by regulating fusion and fission processes) and turnover through autophagy.
AMPK (adenosine monophosphate (AMP)- activated protein kinase)
AMPK acts as the central energy switch (a cellular energy sensor), regulating how energy is produced and used in the body. AMPK has a crucial role in mitochondrial homeostasis, controlling major steps in biogenesis and degradation. It is directly connected with mitophagy, by which it recycles essential nutrients from dysfunctional mitochondria.
(Mitophagy: The removal of damaged mitochondria through autophagy is called mitophagy; critical for maintaining proper cellular functions.)
Oxidative damage induced by mitochondrial poisons indirectly activates AMPK, leading to the activation of mitochondrial fision factor protein, which triggers mitochondrial fragmentation and in turn, mitophagy.
Mitochondrial Sirtuins
Sirtuins are a family of NAD+ dependent deacylases and ADp-ribosyyltransferases. They regulate the cell cycle, DNA repair, cell survival and apoptosis. We have seven sirtuins, whereby 3 are located in mitochondria, SIRT3, SIRT4 and SIRT5.
These three SIRTs orchestrate numerous aspects of mitochondrial biology, including redox balance, metabolism homeostasis, and mitochondrial dynamics.
Mitochondria -linked Diseases:
1. Primary Mitochondrial Disorders
Primary Mitochondrial Disorders are diseases where mitochondrial gene defects are responsible for disease development. The diseases vary greatly in clinical expression but neuromuscular features are quite dominate. Some diseases are:
- Chronic progressive external ophthalmoplegia
- Deafness
- Leber hereditary optic syndrome
- Leigh diseases
- MELAS (Mitochondrial encephalomyopathy)
- MERRF (Mycoclonic epilepsy)
- Mycoclonic epilepsy with ragged red fibers…..
2. Mitochondrial Dysfunction Diseases
- Most age- linked degenerative neurological disease (Alzheiner disease, Parkinson’s disease)
- Malignant tumours and premalignat states
- Congestive heart failure and cardiomyopathy
- Muscular dystrophy
- Motor neurone disease (ALS)
3. Mitochondrial-linked Pathologies
- Low functioning autism, epilepsy
- Metabolic syndrom, insulin resistance and type 2 diabetes, obesity, fatty liver
- Chronic fatigue sysndrome and fibromyalgia
- Nervous sytem injury / neuropathies, including multiple sclerosis and cancer chemotherapy induced neuropathy
- Hypothyroidism, clinical and especially subclinical
- Increased risk of infections
- Chronic kidney disease, hypertension
- Huntington’s disease
- Schizophrenia and bipolar disorder; other conditions linked to neuroinflammation including depression
- Sarcopenia; myopathy, including statin induced
- Ischaemic diseases, reperfusion injury; peparation for cardiac surgery; heart rhthm disorders
- Migraine headache prevention
- Chronic stress response
- Insomnia due to hypthalamic supression
Neustadt, J., & Pieczenik, S. R. (2008). Review Medication-induced mitochondrial damage and disease, 780–788. https://doi.org/10.1002/mnfr.200700075
Tests
Acylcarnitines in Plasma
Sign of mitochondrial dysfunction is:
- Low free carnitine
- Elevated acyl : free carnitine ratio
- Elevations suggestive of disrupted fatty acid oxidation
Lactate and Pyruvate Analysis in Blood
Lactic acid and pyruvate elevation in blood can be an important, albeit non-specific, marker of mitochondrial disease. Elevated levels of lactate are not seen in all types of Mitochondrial Diseases which means that a normal result does not rule out Mitochondrial Disease.
- Raised Lactate with L/P 10-20 indicates a disorder of pyruvate metabolism such as PDH deficiency
- Raised Lactate with L/P of > 20 indicates a disorder of oxidative phosphorylation
Provocative Clinical Testing
Carbohydrate loading with glucose or fructose followed by serial measurements of plasma lactate, pyruvate, and alanine can unmask mitochondrial disease.
Ammonia
Elevated Ammonia levels (>40 μg/dL) are seen in urea acid cycle disorders, organic acid disorders.
Creatine Kinase
Creatine kinase is often mildly elevated with muscle involvement.
BUN
Low BUN indicates failure of urea acid cycle, either primary or secondary.
CBC (Complete Blood Cell Count)
Neutropenia, thrombocytopenia and anemia are often seen in organic acid disorders.
Organic acid test in urine
Signs of mitochondrial dysfunction are:
- Evaluated Kreb Cycle, Glycolic Acid, and /or Mitochondrial Amino Acid metabolites- for example elevated succinic, fumerate, malate or other markers.
- Evaluated Lactic and Pyruvic Acid
- Low 3-Hydroxy-3-methylglutaric acid = CoQ10
Amimo Acid in Plasma
Signs of mitochondrial dysfunction are:
- Elevated alanine
- Elevated glycine, proline, sarcosine or tyrosine
Haas, R. H., Parikh, S., Falk, M. J., Russell, P., Wolf, N. I., Darin, N., … Naviaux, R. K. (2010). The In-Depth Evaluation of Suspected Mitochondrial Disease: The Mitochondrial Medicine Society’s Committee on Diagnosis. Mol Genet Metab (Vol. 94). http://doi.org/10.1016/j.ymgme.2007.11.018.
Treatments
Addressing the underlying causes of mitochondrial dysfunction
- Avoiding too much free radical production
- Getting excellent and sufficient sleep so that mitochondrion can repair themselves
- Excellent nutrition in respect to micronutrients.
- Protection of mitochondrial function by Nrf2, increasing reduced glutathione production, increasing mitochondrial antioxidants.
- Stabilising blood sugar levels
- Identifying allergies, intolerances and food sensitivities
- Detoxifying to unload heavy metals, pesticides, drugs, (alcohol, tobacco etc) and volatile organic compounds, all of which negatively influence mitochondrial function.
- Addressing the secondary damage caused by mitochondrial dysfunction such as immune disturbances resulting in allergies and autoimmunity, poor digestive function, hormone gland failure, slow liver detoxification.
Exercise
Aerobic Exercise
Aerobic exercise such as running, jogging, biking, swimming is known to significantly increase large amounts of muscle mitochondria.
Resistance
Resistance training such as Gross Fit, weight training greatly increases the mitochondria’s ability for greater biogenesis beyond what is accomplished with aerobic exercise.
High Intensity Interval Training
High intensity interval training is characterized by repeated bursts of intense exercise in between short rest intervals. Examples include soccer, tennis, basketball. This form of exercise greatly enhances mitochondrial energy production.
Supplementation
Nutrient cofactors needed for healthy mitochondrial function:
PDH complex: CoA (from B5), NAD+ (contains B3), FAD+ (contains B2), lipoic acid and ThPP (thiamine pyrophosphate, contains B1)
Krebs cycle: B1, B2, B3, B5, Fe, Mg, Mn, cysteine and lipoic acid
ETC and electron shuttle: CoQ10, Fe-S clusters (containe Fe and cysteine), B2, B3, Cu, Mg
Fatty acid metabolism: l-carnitine especially
L-Carnitine
L-carnitine plays an important role in energy production by conjugating fatty acids for transport into the mitochondria. Tissue L-carnitine levels have been found to decline with age in humans and animals. L-carnitine supplementation may cause mild gastrointestinal symptoms, including nausea, vomiting, abdominal cramps, and diarrhea.
Adults: 330–990 mg/dose two or three times per day, children: 20–100 mg/kg/d divided into two or three doses
Fonslow, B. R., Stein, B. D., Webb, K. J., Xu, T., Choi, J., Kyu, S., & Iii, J. R. Y. (2013). NIH Public Access. Curr Treat Options Neurol ., 10(1), 54–56. http://doi.org/10.1038/nmeth.2250.Digestion
Acetyl-L-Carnitine
Acetyl-L-Carnitine is well-known for its ability to protect the mitochondria. Acetyl-L-carnitine (ALC) is derived from the acetylation of carnitine in the mitochondria. Carnitine acetylation helps eliminate oxidative products from the body.
50-100 mg/kg/day
Fonslow, B. R., Stein, B. D., Webb, K. J., Xu, T., Choi, J., Kyu, S., & Iii, J. R. Y. (2013). NIH Public Access. Curr Treat Options Neurol ., 10(1), 54–56. http://doi.org/10.1038/nmeth.2250.Digestion
Sulforaphane
Sulforaphane is found in cruciferous vegetables mainly broccoli and broccoli sprouts in its storage form of Glucoraphanin. Glucoraphanin is then converted by the enzyme myrosinase into sulforaphane. Heating can destroy the enzyme myrosinase in broccoli.
Kalpana Deepa Priya, D., Gayathri, R., Gunassekaran, G. R., & Sakthisekaran, D. (2011). Protective role of sulforaphane against oxidative stress mediated mitochondrial dysfunction induced by benzo(a)pyrene in female Swiss albino mice. Pulmonary Pharmacology and Therapeutics, 24(1), 110–117. http://doi.org/10.1016/j.pupt.2010.09.002
Tarozzi, A., Angeloni, C., Malaguti, M., Morroni, F., Hrelia, S., & Hrelia, P. (2013). Sulforaphane as a Potential protective phytochemical against neurodegenerative diseases. Oxidative Medicine and Cellular Longevity, 2013. http://doi.org/10.1155/2013/415078
Resveratrol
Resveratrol is a naturally occurring polyphenol found in more than 70 species of plants, including grapes, cranberries and peanuts, which was shown to confer diverse physiological effects such as cancer protection, microvascular protection, neuroprotection, cardioprotection, antidiabetic protection and mitochondrial function support.
Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., … Auwerx, J. (2006). Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1?? Cell, 127(6), 1109–1122. http://doi.org/10.1016/j.cell.2006.11.013
Resveratrol is the best SIRT 3, SIRT 4 and SIRT 5 inducer and therefore highly beneficial for mitochondrial protection.
Alcaín2, J. M. V. and F. J. (2013). Sirtuin activators and inhibitors, 38(5), 349–359. https://doi.org/10.1002/biof.1032.Sirtuin
CoQ10 (Ubiquinol)
Coenzyme Q10 supports mitochondrial energy production in the electron transport chain by carrying electrons from cytochrome to cytochrome in order for ATP to be produced in the mitochondria. Without CoQ10, there is no electron transfer
5-10mg/kg/day
Fonslow, B. R., Stein, B. D., Webb, K. J., Xu, T., Choi, J., Kyu, S., & Iii, J. R. Y. (2013). NIH Public Access. Curr Treat Options Neurol ., 10(1), 54–56. http://doi.org/10.1038/nmeth.2250.Digestion
Alpha-Lipoic acid
Alpha-Lipoic Acid (ALA) is a mitochondrial fatty acid that is highly involved in energy metabolism. It is a potent anti-oxidant compound and works with mitochondria and the body's natural anti-oxidant defenses.
300-600mg/day
Liu, J. (2008). The effects and mechanisms of mitochondrial nutrient ??-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: An overview. Neurochemical Research, 33(1), 194–203. http://doi.org/10.1007/s11064-007-9403-0
Quercetin
The bioflavonoid quercetin has emerged as a mitochondrial-enhancing agent. In a mouse model of Alzheimer's disease, quercetin lessened learning and memory deficits, reduced senile plaques, and counteracted mitochondrial dysfunction.
Sandhir, R., & Mehrotra, A. (2013). Quercetin supplementation is effective in improving mitochondrial dysfunctions induced by 3-nitropropionic acid: Implications in Huntington’s disease. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1832(3), 421–430. http://doi.org/10.1016/j.bbadis.2012.11.018
Carrasco-Pozo, C., Mizgier, M. L., Speisky, H., & Gotteland, M. (2012). Differential protective effects of quercetin, resveratrol, rutin and epigallocatechin gallate against mitochondrial dysfunction induced by indomethacin in Caco-2 cells. Chemico-Biological Interactions, 195(3), 199–205. http://doi.org/10.1016/j.cbi.2011.12.007
D-Ribose
Ribose is a naturally occurring 5-carbon sugar produced in the body from glucose. In addition to serving as the carbohydrate backbone for ribonucleic acid (RNA) and deoxyribonucleic acid (DNA), ribose is also an essential ingredient in the manufacture of ATP.
The presence of ribose in the cell stimulates the metabolic pathway our bodies use to actually produce the ATP we require.
5g 3x/day for 6 weeks, then 5 g 2x/day for 6 more weeks
Teitelbaum, J. (2008). Enhancing Mitochondrial Function With D-Ribose. Integrative Medicine, 7(2), 46–51.
N-Acetyl Cysteine
The neuroprotective properties of NAC may be related to its neurogenesis-inducing ability, which is likely related to mitochondria-protective mechanisms.
Lee, C. P. (1999). Following Traumatic Brain Injury in Rats, 16(11).
Fucoidan
Fucoidan decreased reactive oxygen species, lipid peroxidation, mitochondrial swelling and increased the activities of antioxidant enzymes and glutathione levels and normalized the activities of mitochondrial TCA cycle and respiratory complex enzymes in an animal model of hyperoxaluria.
Veena, C. K., Josephine, A., Preetha, S. P., Rajesh, N. G., & Varalakshmi, P. (2008). Mitochondrial dysfunction in an animal model of hyperoxaluria: A prophylactic approach with fucoidan. European Journal of Pharmacology, 579(1-3), 330–336. http://doi.org/10.1016/j.ejphar.2007.09.044
Melatonin
Melatonin is a potent antioxidant protecting mitochondria, which are exposed to abundant free radicals. It also increases reduced glutathione, SOD and GPx.
Low dose 1 to 3 mg/day
Ozone
Ozone is a powerful mitochondrial stimulant. The fundamental underlying cause behind all degenerative disease from diabetes to heart disease to cancer is decreased mitochondrial energy production. Ozone can often correct this problem. Ozone also increases antioxidant protection by activating Nrf2 more than any other therapy. Under conditions of stress or growth factor stimulation, activation of Nrf2 counteracts the increased reactive oxygen species production in mitochondria. Any Nrf2 activator, was found to promote mitophagy, thereby contributing to the overall mitochondrial homeostasis.
Dinkova-kostova, A. T., & Abramov, A. Y. (2015). Free Radical Biology and Medicine The emerging role of Nrf2 in mitochondrial function. Free Radical Biology and Medicine, 88, 179–188. https://doi.org/10.1016/j.freeradbiomed.2015.04.036
Cancer
Mitochondrial defects can contribute to cancer glycolysis:
Mitochondrial DNA (mtDNA) mutations lead to malfunction in respiration and oxidative phosphorylation. Cancer cells oxidative phosphorylation is already impaired and they relay on glycolysis. So mutations in mtDNA even further contribute to glycolysis. Several factors contribute to the high mutation rates in mtDNA. These factors include: the close physical location of mtDNA to the ROS (Reactive Oxygen Species) generation sites in the mitochondria, lack of histone protection and weak DNA repair capacity in the mitochondria. Frequent mtDNA mutations have been observed in: prostate, breast cancer, gastric cancer and leukemia.
Mitochondria integrate numerous pro-survival and pro-death signal, therby exerting a decisive control over several biochemical cascades leading to cell death and particular the intrinsic pathway of apoptosis.
In most cancers, mitochondria numbers fall, thus resistance to chemotherapeutic drugs or ionizing radiation can possibly occur. That is, cancers that have markedly reduced mitochondrial mass may be untreatable by any orthodox treatment, except by surgical means or through directly targeting the mitochondria in malignant cells only.
This is a very specific chapter and was added for your information only. We decided to add this information about mitochondrial dysfunction as it is very often discussed as a cause of disease.
No quiz required.
Further reading recommended:
Aricle: Mitochondrial dysfunction the driving force behind disease, what can we do? https://www.trulyheal.com/mitochondrial-dysfunction-the-driving-force-behind-disease-what-can-we-do/