Mitotropic Substances: History
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Daniel Schniertshauer
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Susanne Wespel
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Jörg Bergemann

Mitotropic substances, or so-called mitoceuticals, describe substances whose mode of action is directed at the bioenergetic processes of the mitochondria and are, in part, essential for their function. The term mitoceuticals, created by Dr. Franz Enzmann, encompasses several groups of mitotropic substances, which have a versatile potential and form the basis for a preventive and therapeutic approach in mitochondrial medicine. They act non-specifically and reach all mitochondria in the organism. The best-known substances include electron and proton carriers, such as ubiquinol/ubiquinone (coenzyme Q10; CoQ10), vitamins, minerals, and micronutrients. Mitoceuticals are substances that are part of the natural metabolic system of a cell anyway. They are used both preventively and therapeutically for accompanying treatment. In both cases, the aim is to compensate for an existing mitochondrial dysfunction. In the meantime, there are a large number of mitotropic substances and even more studies on them.

  • antioxidants
  • dysfunctions
  • mitochondria
  • mitotropic

1. Electron and Proton Carrier

Electron and proton carriers are proteins and enzymes with the ability to transport electrons or protons and, in some cases, both. This is often due to their redox-active character [1]. The UCPs mentioned in point 1.2 The respiratory chain, which separates oxidative phosphorylation from ATP synthesis, also belong to the group of (mitochondrial) proton carriers [2]. Electron and proton carriers are essential for the generation of ATP by oxidative phosphorylation since they ensure the necessary transport of electrons along complexes I to IV and the mobile components ubiquinone (CoQ) and cytochrome c and the establishment of a proton gradient across the inner mitochondrial membrane [1]. In addition to the mentioned substances, such as CoQ10 and UCPs, nicotinamide mononucleotide (NMN), a molecule from the family of B3 vitamins, for example, also belongs to this group.

2. Vitamins

Vitamins are organic compounds that an organism needs not as energy carriers but for other vital functions. They are involved in many reactions, influence the immune system, for example, and are indispensable in building cells of all human tissue. With the exception of vitamins D and B3, which the human body synthesizes itself, all other vitamins must be taken up completely with food, as they are essential substances. Some vitamins are supplied to the body as precursors, so-called provitamins, which are first converted into their active form in the body [3]. This research focuses on the class of B, C, and E vitamins because of their importance for mitochondrial medicine. Chemically, vitamins do not form a uniform group of substances. Since they are quite complex organic molecules, they do not occur in inanimate nature. They must first be formed by plants, bacteria, or animals [4]. According to their chemical function, the 13 known vitamins can be classified as free radical scavengers, coenzymes, or precursors of messenger substances and dyes. A further subdivision is made into fat-soluble (lipophilic) and water-soluble (hydrophilic) vitamins. In contrast to other biomolecules, such as proteins or nucleic acids, vitamins do not have a uniform structure and differ greatly from one another structurally. Thus, among the vitamins, there are steroids, isoprenoids, pyrimidines, pyridines, sugar acids, and urea derivatives. For better differentiation, several related compounds with comparable properties are grouped under a single vitamin [5].
  • Molecular mechanism/Biological function
Vitamins are needed by the body to maintain its many vital functions. Depending on the vitamin, the daily requirement is between 20 µg (vitamin D) and 100 mg (vitamin C) and is influenced by individual circumstances, such as body weight, the amount of physical work or even existing diseases. If the requirement is not met or exceeded, diseases may occur, which are called vitaminoses. The essential functions of vitamins include controlling the metabolism of protein, carbohydrates, and fat. They are also involved in the formation of endogenous substances, such as enzymes, hormones, and blood cells [5].
Many B vitamins are mitotropic substances—including vitamin B1 (thiamine), B2 (riboflavin), B3 (niacinamide), and B6 (pyroxine, pyrixodal, and pyridoxamine). The functions of these compounds, which are essential for the body, include, for example, pacemaking in cellular carbohydrate metabolism, inhibition of protein glycosylation, and excitation and transmission of stimuli in the peripheral nervous system by thiamine. Riboflavin is involved in cellular metabolism in the form of the flavin coenzymes flavin adenine dinucleotide (FAD) and flavin adenine mononucleotide (FAM). Here, flavin coenzymes are indispensable for the course of dozens of enzymatically catalyzed oxidations and reduction reactions and, thus, for the intracellular oxidative balance. They are able to act as electron acceptors or donors, depending on the direction of the reaction. Thus, riboflavin performs an essential role in the mitochondrial respiratory chain. Furthermore, it is involved in the metabolism of other B vitamins, including the formation of niacinamide. As a coenzyme component of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), this vitamin is also involved in numerous enzymatic reactions in metabolism and performs a key role in energy formation in the mitochondria. In this process, it works closely together with CoQ10. Among the B6 vitamins, pyridoxal phosphate and pyridoxamine phosphate are particularly important in relation to human metabolism since they assume coenzyme functions in more than 100 enzymatic reactions. Due to the great importance of vitamin B6 in amino acid metabolism, a deficiency of B6 can cause growth disorders and atrophy of the musculature, thymus gland, and gonads, especially in cases of severe deficiency [3].
Vitamin C (ascorbic acid), an organic acid, belongs to the group of hydrophilic vitamins. The importance of vitamin C for our immune system is well known. However, this basic substance fulfills a multitude of other vital functions in the body. Recent research has come to the conclusion that vitamin C is much more important as an antioxidant and especially as an enzyme cofactor than previously thought. For example, as a cofactor, this vitamin plays a key role in the formation of collagen, in immune defense, and in the formation of cerebral hormones and neurotransmitters. In addition to these functions, vitamin C is a very effective radical scavenger in the body [3].
Vitamin E (tocopherol) is a grouping of eight vitamins, all of which are lipophilic in character and have tocopherol activity. Most E vitamins have antioxidant activity [6][7]. This is also one of its most important functions. Through its function as a radical scavenger, tocopherol is able to protect polyunsaturated fatty acids in membrane lipids, lipoproteins and depot fat from destruction by oxidation (lipid peroxidation). In this process, tocopherol itself becomes an inert mesomeric stabilized radical. The tocopherol radical is then reduced to form an ascorbate radical. The ascorbate radical is regenerated with the help of glutathione (GSH) [8].
  • Studies on the efficacy of Vitamins
In addition to the studies on electron/proton carriers, vitamins also show a positive record of use in mitochondrial medicine, particularly in the production of ROS and, thus, protection from oxidative damage.
For example, vitamin E reacts more rapidly with peroxide radicals than do polyunsaturated fatty acid molecules, thus protecting mitochondrial membranes from excessive oxidative damage [9]. In addition, it reduces the production of ROS in mitochondria [10]. Vitamin E also protects against hyperthyroidism. A condition which leads to increased mitochondrial ROS production and, consequently, oxidative damage [9]. It also prevents hyperthyroidism-induced reduction in mitochondrial complexes and ensures that cellular functions are maintained [9]. This could be mediated by the ability of vitamin E to scavenge ROS. Analysis of the effects of electron chain inhibitors on the mitochondrial release rate of H2O2 suggests that vitamin E may influence the level of autoxidizable carriers. Moreover, vitamin E is preferentially incorporated into mitochondrial membranes [9].
In contrast, vitamin C acts as a mild pro-oxidant that can produce free radicals and consequently stimulates mitochondrial biogenesis [11]. It is also known that vitamin C can be highly concentrated in mitochondria by means of the specific mitochondrial sodium-vitamin C transporter 2 (SVCT2). In this way, it can reduce the proliferation of cancer stem cells (CSCs) by more than 90% in a combination therapy together with doxycycline and azithromycin [11].
Not in humans, but in a spinocerebellar ataxia type 3 (SCA3) Drosophila model, polyglutamine (polyQ)-mediated mitochondrial damage leading to loss of neurons and damage to non-neuronal cells could be successfully treated with vitamin B6 [12]. An abnormality of vitamin B6 metabolic pathways caused by pathological polyQ expression could thus be bypassed. Active vitamin B6 is involved in hundreds of enzymatic reactions and is very important for maintaining mitochondrial activities. In this research, vitamin B6 supplementation suppressed mitochondrial damage in viscera and inhibited cellular polyQ aggregates in fat bodies, indicating a promising therapeutic strategy for the treatment of polyQ [12].

3. Minerals

Minerals are vital nutrients, usually present as ions or inorganic compounds, which the organism cannot produce itself. They are essential for many functions, such as the formation of bones, the maintenance of osmotic pressure, or the formation of hormones [13]. Minerals, of which 22 are considered physiologically necessary for the human body, are divided into two groups in the body, so-called bulk elements and trace elements. Bulk elements are represented with a higher concentration than 50 mg/kg body weight. Trace elements, on the other hand, have a required concentration of less than 50 mg/kg body weight. As bulk elements are usually ionized in the aqueous milieu, they are referred to as electrolytes. Trace elements, on the other hand, are metals that are absorbed by the body in very small amounts (often only a few micrograms) [13][14].
  • Molecular mechanism/Biological function
An important bulk element in mitochondrial medicine is magnesium (Mg2+). It is indispensable for the proper functioning of numerous biochemical processes. The physiological spectrum of action of magnesium is enormous because it is involved as a component or cofactor in several hundred enzymatic reactions. These include, among others, the production of nucleic acids, participation in all reactions triggered by ATP by stabilizing the produced ATP molecule, which is mainly present as a complex with a central magnesium ion [3][15]. Free Mg2+ ions influence the potential at cell membranes and act as second messengers in the immune system. They stabilize the resting potential of excitable muscle and nerve cells and the cells of the autonomic nervous system [16]. In addition, along with CoQ10, and B vitamins 2 and 3, it performs an important role in the mitochondrial respiratory chain, where it activates diverse enzymes. For example, the activation of thiamine to the co-enzymatically active thiamine diphosphate requires a magnesium-dependent thiamine kinase [3].
Dietary Mg intake has been shown to be often inadequate in the Western population. This inadequate intake has been associated with a number of adverse health effects, including restlessness, nervousness, irritability, lack of concentration, fatigue, general feeling of weakness, headaches, but also hypertension, cardiovascular disease, muscle cramps, and type II diabetes [15][16]. In addition to bulk elements, such as magnesium, trace elements, such as copper or zinc, also perform an important role in mitochondrial function.
  • Studies on the efficacy of Minerals
The fact that mitochondria have been shown to be able to both accumulate and release Mg2+ makes them an important intracellular Mg2+ store [17]. Together with recent advances in the field of Mg2+ transporter research, which have led to the identification of the plasma membrane Mg2+ transporter Solute Carrier Family 41 Member 1 (SLC41A1), the mitochondrial Mg2+ efflux system SLC41A3, the mitochondrial Mg2+ influx channel Mrs2, and a mitochondrial Mg2+ exporter, highlights the importance of gastensium balance in mitochondrial function [17]. Mg2+ has been shown to enhance the activity of three major mitochondrial dehydrogenases involved in energy metabolism. While the activities of isocitrate dehydrogenase (IDH) and 2-oxoglutarate dehydrogenase complex (OGDH) are directly stimulated by the Mg2+ isocitrate complex or are stimulated by free Mg2+, the activity of the pyruvate dehydrogenase complex (PDH) is stimulated indirectly via the stimulatory effect of Mg2+ on pyruvate dehydrogenase phosphatase, which dephosphorylates and thus activates the pyruvate decarboxylase of PDH. OGDH functions as an important mitochondrial redox sensor [17].
Dysregulation of these Mg transporters and channels is caused by and also contributes to impaired Mg homeostasis [18]. Thus, decreased levels of free ionized intracellular Mg ([Mg]i) could cause Mg stores, such as mitochondria, to release Mg via SLC41A3 [18]. Decreased mitochondrial Mg levels ([Mg]m) could, in turn, impair further Mg/MgATP-associated mitochondrial signaling and function, which could explain the mitochondrial overproduction of reactive oxygen species (ROS) and decreased ATP levels observed in Mg-deficient mice [18]. Liu et al. recently reported that Mg deficiency in diabetic mice increases mitochondrial oxidative stress and contributes to cardiac diastolic dysfunction [18]. In a low Mg diet-induced mouse model, mitochondrial oxidative stress was also found to contribute to cardiac diastolic dysfunction. Mg supplementation was able to suppress mitochondrial ROS overproduction and reverse diastolic dysfunction, and, therefore, in this case, Mg acts as a mitochondrial antioxidant [18].
The relationship between low Mg status, which is caused by several factors (for example, low Mg intake and absorption, genetic defects in Mg transporters, obesity, type 2 diabetes mellitus (T2DM)) and oxidative stress was also shown by Barbagallo et al. [19].
Thus, low Mg status may trigger increased free radical production (ROS), oxidative damage, and activation of redox signaling. The increased oxidative stress, in turn, can lead to the release of inflammatory mediators, which represent a state of chronic low-level inflammation considered to accompany aging and termed “inflammaging” [19].

4. Further Mitotropic Substances

In addition to the substances already mentioned, there are now a growing number of other compounds whose efficacy on the mitochondria has been confirmed. These include resveratrol and spermidine.

This entry is adapted from the peer-reviewed paper 10.3390/cimb45050250

References

  1. Bentinger, M.; Tekle, M.; Dallner, G. Coenzyme Q—Biosynthesis and functions. Biochem. Biophys. Res. Commun. 2010, 396, 74–79.
  2. Nedergaard, J.; Ricquier, D.; Kozak, L.P. Uncoupling proteins: Current status and therapeutic prospects. EMBO Rep. 2005, 6, 917–921.
  3. Enzmann, F. Das MitoMed-Konzept—Mse Pharmazeutika GmbH. Available online: https://www.mse-pharma.de/mitomed-konzept/ (accessed on 8 January 2023).
  4. Mora, J.R.; Iwata, M.; von Andrian, U.H. Vitamin effects on the immune system: Vitamins A and D take centre stage. Nat. Rev. Immunol. 2008, 8, 685–698.
  5. Thieme Verlag. Available online: https://viamedici.thieme.de/lernmodul/548911/538843/vitamine+und+vitaminosen+grundlagen (accessed on 22 December 2022).
  6. Vitamin E: Physiologie, Funktionen, Vorkommen, Referenzwerte und Versorgung in Deutschland. Available online: https://www.ernaehrungs-umschau.de/fileadmin/Ernaehrungs-Umschau/pdfs/pdf_2010/11_10/EU11_2010_608_615.qxd.pdf (accessed on 14 December 2022).
  7. Pietrzik, K.; Golly, I.; Loew, D. Handbuch Vitamine: Für Prophylaxe, Therapie und Beratung, 1st ed.; Urban&Fischer, Elsevier: München, Germany, 2008; ISBN 9783437553615.
  8. EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA). Scientific Opinion on Dietary Reference Values for vitamin E as α-tocopherol. EFSA J. 2015, 13, 4149–4221.
  9. Napolitano, G.; Fasciolo, G.; Di Meo, S.; Venditti, P. Vitamin E Supplementation and Mitochondria in Experimental and Functional Hyperthyroidism: A Mini-Review. Nutrients 2019, 11, 2900.
  10. Majima, H.J.; Indo, H.P.; Suenaga, S.; Matsui, H.; Yen, H.-C.; Ozawa, T. Mitochondria as Possible Pharmaceutical Targets for the Effects of Vitamin E and its Homologues in Oxidative Stress-Related Diseases. Curr. Pharm. Des. 2011, 17, 2190–2195.
  11. Fiorillo, M.; Tóth, F.; Sotgia, F.; Lisanti, M.P. Doxycycline, Azithromycin and Vitamin C (DAV): A potent combination therapy for targeting mitochondria and eradicating cancer stem cells (CSCs). Aging 2019, 11, 2202–2216.
  12. Nan, Y.; Lin, J.; Cui, Y.; Yao, J.; Yang, Y.; Li, Q. Protective role of vitamin B6 against mitochondria damage in Drosophila models of SCA. Neurochem. Int. 2021, 144, 104979.
  13. Zoroddu, M.A.; Aaseth, J.; Crisponi, G.; Medici, S.; Peana, M.; Nurchi, V.M. The essential metals for humans: A brief overview. J. Inorg. Biochem. 2019, 195, 120–129.
  14. Rehner, G.; Daniel, H. Biochemie Der Ernährung, 3rd ed.; Springer: Berlin, Germany, 2010; ISBN 9783827422170.
  15. Boyle, N.B.; Lawton, C.; Dye, L. The Effects of Magnesium Supplementation on Subjective Anxiety and Stress—A Systematic Review. Nutrients 2017, 9, 429.
  16. Li, F.-Y.; Chaigne-Delalande, B.; Kanellopoulou, C.; Davis, J.C.; Matthews, H.F.; Douek, D.C.; Cohen, J.I.; Uzel, G.; Su, H.C.; Lenardo, M.J. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature 2011, 475, 471–476.
  17. Pilchova, I.; Klacanova, K.; Tatarkova, Z.; Kaplan, P.; Racay, P. The Involvement of Mg2+ in Regulation of Cellular and Mitochondrial Functions. Oxid. Med. Cell. Longev. 2017, 2017, 6797460.
  18. Liu, M.; Dudley, S.C., Jr. Magnesium, Oxidative Stress, Inflammation, and Cardiovascular Disease. Antioxidants 2020, 9, 907.
  19. Barbagallo, M.; Veronese, N.; Dominguez, L.J. Magnesium in Aging, Health and Diseases. Nutrients 2021, 13, 463.
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