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== Effects on ALS == | == Effects on ALS == | ||
| − | Human UBIAD1 localizes to mitochondria and converts vitamin K1 to vitamin K2. Vitamin K2 is best known as a cofactor in blood coagulation, but in bacteria it is a membrane-bound electron carrier. Whether vitamin K2 exerts a similar carrier function in eukaryotic cells is unknown. We identified Drosophila UBIAD1/Heix as a modifier of pink1, a gene mutated in Parkinson’s disease that affects mitochondrial function. We found that vitamin K2 was necessary and sufficient to transfer electrons in Drosophila mitochondria. Heix mutants showed severe mitochondrial defects that were rescued by vitamin K2, and, similar to ubiquinone, vitamin K2 transferred electrons in Drosophila mitochondria, resulting in more efficient adenosine triphosphate (ATP) production. Thus, mitochondrial dysfunction was rescued by vitamin K2 that serves as a mitochondrial electron carrier, helping to maintain normal ATP production. | + | Human UBIAD1 localizes to mitochondria and converts vitamin K1 to vitamin K2. Vitamin K2 is best known as a cofactor in blood coagulation, but in bacteria it is a membrane-bound electron carrier. Whether vitamin K2 exerts a similar carrier function in eukaryotic cells is unknown. We identified Drosophila UBIAD1/Heix as a modifier of pink1, a gene mutated in Parkinson’s disease that affects mitochondrial function. We found that vitamin K2 was necessary and sufficient to transfer electrons in Drosophila mitochondria. Heix mutants showed severe mitochondrial defects that were rescued by vitamin K2, and, similar to ubiquinone, vitamin K2 transferred electrons in Drosophila mitochondria, resulting in more efficient adenosine triphosphate (ATP) production. Thus, mitochondrial dysfunction was rescued by vitamin K2 that serves as a mitochondrial electron carrier, helping to maintain normal ATP production. |
Vitamin K2 is a possible treatment for mitochondrial pathologies such as Parkinson's disease and amyotrophic lateral sclerosis. | Vitamin K2 is a possible treatment for mitochondrial pathologies such as Parkinson's disease and amyotrophic lateral sclerosis. | ||
| − | K2 may protect from Vitamin D3 toxicity if high amounts of D3 is supplemented. | + | K2 may protect from Vitamin D3 toxicity if high amounts of D3 is supplemented. |
| − | Vitamin K2 may induce mitochondria-mediated apoptosis: ''Here, we identified Bcl-2 antagonist killer 1 (Bak) as a molecular target of VK2-induced apoptosis. VK2 directly interacts with Bak and induces mitochondrial-mediated apoptosis. Although Bak and Bcl-2-associated X protein (Bax), another member of the Bcl-2 family, are generally thought to be functionally redundant, only Bak is necessary and sufficient for VK2-induced cytochrome c (cyt c) release and cell death. Moreover, VK2-2,3 epoxide, an intracellular metabolite of VK2, was shown to covalently bind to the cysteine-166 residue of Bak. Several lines of evidence suggested that the covalent attachment of VK2 is critical for apoptosis induction. Thus this study reveals a specific role for Bak in mitochondria-mediated apoptosis. This study also provides insight into the anticancer effects of VK2 and suggests that Bak may be a potential target of cancer therapy.'' | + | Vitamin K2 may induce mitochondria-mediated apoptosis: ''Here, we identified Bcl-2 antagonist killer 1 (Bak) as a molecular target of VK2-induced apoptosis. VK2 directly interacts with Bak and induces mitochondrial-mediated apoptosis. Although Bak and Bcl-2-associated X protein (Bax), another member of the Bcl-2 family, are generally thought to be functionally redundant, only Bak is necessary and sufficient for VK2-induced cytochrome c (cyt c) release and cell death. Moreover, VK2-2,3 epoxide, an intracellular metabolite of VK2, was shown to covalently bind to the cysteine-166 residue of Bak. Several lines of evidence suggested that the covalent attachment of VK2 is critical for apoptosis induction. Thus this study reveals a specific role for Bak in mitochondria-mediated apoptosis. This study also provides insight into the anticancer effects of VK2 and suggests that Bak may be a potential target of cancer therapy.'' [3] |
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== References == | == References == | ||
| + | |||
| + | [1] | ||
| + | <bibtex> | ||
| + | @article{Masterjohn2007, | ||
| + | abstract = {The dose of vitamin D that some researchers recommend as optimally therapeutic exceeds that officially recognized as safe by a factor of two; it is therefore important to determine the precise mechanism by which excessive doses of vitamin D exert toxicity so that physicians and other health care practitioners may understand how to use optimally therapeutic doses of this vitamin without the risk of adverse effects. Although the toxicity of vitamin D has conventionally been attributed to its induction of hypercalcemia, animal studies show that the toxic endpoints observed in response to hypervitaminosis D such as anorexia, lethargy, growth retardation, bone resorption, soft tissue calcification, and death can be dissociated from the hypercalcemia that usually accompanies them, demanding that an alternative explanation for the mechanism of vitamin D toxicity be developed. The hypothesis presented in this paper proposes the novel understanding that vitamin D exerts toxicity by inducing a deficiency of vitamin K. According to this model, vitamin D increases the expression of proteins whose activation depends on vitamin K-mediated carboxylation; as the demand for carboxylation increases, the pool of vitamin K is depleted. Since vitamin K is essential to the nervous system and plays important roles in protecting against bone loss and calcification of the peripheral soft tissues, its deficiency results in the symptoms associated with hypervitaminosis D. This hypothesis is circumstantially supported by the observation that animals deficient in vitamin K or vitamin K-dependent proteins exhibit remarkable similarities to animals fed toxic doses of vitamin D, and the observation that vitamin D and the vitamin K-inhibitor Warfarin have similar toxicity profiles and exert toxicity synergistically when combined. The hypothesis further proposes that vitamin A protects against the toxicity of vitamin D by decreasing the expression of vitamin K-dependent proteins and thereby exerting a vitamin K-sparing effect. If animal experiments can confirm this hypothesis, the models by which the maximum safe dose is determined would need to be revised. Physicians and other health care practitioners would be able to treat patients with doses of vitamin D that possess greater therapeutic value than those currently being used while avoiding the risk of adverse effects by administering vitamin D together with vitamins A and K.}, | ||
| + | author = {Masterjohn, Christopher}, | ||
| + | doi = {10.1016/j.mehy.2006.09.051}, | ||
| + | issn = {0306-9877}, | ||
| + | journal = {Medical hypotheses}, | ||
| + | keywords = {Animals,Humans,Models, Biological,Vitamin A,Vitamin A: metabolism,Vitamin D,Vitamin D: toxicity,Vitamin K Deficiency}, | ||
| + | mendeley-groups = {kvitamin}, | ||
| + | month = jan, | ||
| + | number = {5}, | ||
| + | pages = {1026--34}, | ||
| + | pmid = {17145139}, | ||
| + | title = {{Vitamin D toxicity redefined: vitamin K and the molecular mechanism.}}, | ||
| + | url = {http://www.ncbi.nlm.nih.gov/pubmed/17145139}, | ||
| + | volume = {68}, | ||
| + | year = {2007} | ||
| + | } | ||
| + | </bibtex> | ||
| + | |||
| + | |||
| + | [2] | ||
| + | <bibtex> | ||
| + | @article{Lovern2013, | ||
| + | abstract = {UNLABELLED: Quinone compounds act as membrane resident carriers of electrons between components of the electron transport chain in the periplasmic space of prokaryotes and in the mitochondria of eukaryotes. Vitamin K is a quinone compound in the human body in a storage form as menaquinone (MK); distribution includes regulated amounts in mitochondrial membranes. The human brain, which has low amounts of typical vitamin K dependent function (e.g., gamma carboxylase) has relatively high levels of MK, and different regions of brain have different amounts. Coenzyme Q (Q), is a quinone synthesized de novo, and the levels of synthesis decline with age. The levels of MK are dependent on dietary intake and generally increase with age. MK has a characterized role in the transfer of electrons to fumarate in prokaryotes. A newly recognized fumarate cycle has been identified in brain astrocytes. The MK precursor menadione has been shown to donate electrons directly to mitochondrial complex III. | ||
| + | |||
| + | HYPOTHESIS: Vitamin K compounds function in the electron transport chain of human brain astrocytes.}, | ||
| + | author = {Lovern, Douglas and Marbois, Beth}, | ||
| + | doi = {10.1016/j.mehy.2013.07.008}, | ||
| + | issn = {1532-2777}, | ||
| + | journal = {Medical hypotheses}, | ||
| + | keywords = {Astrocytes,Astrocytes: metabolism,Brain,Brain: cytology,Brain: metabolism,Electron Transport,Electron Transport: physiology,Glutamic Acid,Glutamic Acid: metabolism,Humans,Models, Biological,Molecular Structure,NAD(P)H Dehydrogenase (Quinone),NAD(P)H Dehydrogenase (Quinone): metabolism,Quinones,Quinones: metabolism,Ubiquinone,Ubiquinone: metabolism,Vitamin K 1,Vitamin K 1: chemistry,Vitamin K 1: metabolism,Vitamin K 2,Vitamin K 2: chemistry,Vitamin K 2: metabolism,Vitamin K 3,Vitamin K 3: chemistry,Vitamin K 3: metabolism}, | ||
| + | mendeley-groups = {kvitamin}, | ||
| + | month = oct, | ||
| + | number = {4}, | ||
| + | pages = {587--91}, | ||
| + | pmid = {23910074}, | ||
| + | title = {{Does menaquinone participate in brain astrocyte electron transport?}}, | ||
| + | url = {http://www.ncbi.nlm.nih.gov/pubmed/23910074}, | ||
| + | volume = {81}, | ||
| + | year = {2013} | ||
| + | } | ||
| + | </bibtex> | ||
| + | |||
| + | |||
| + | [3] | ||
| + | <bibtex> | ||
| + | @article{Karasawa2013, | ||
| + | abstract = {Vitamin K2 (VK2, menaquinone) is known to have anticancer activity in vitro and in vivo. Although its effect is thought to be mediated, at least in part, by the induction of apoptosis, the underlying molecular mechanism remains elusive. Here, we identified Bcl-2 antagonist killer 1 (Bak) as a molecular target of VK2-induced apoptosis. VK2 directly interacts with Bak and induces mitochondrial-mediated apoptosis. Although Bak and Bcl-2-associated X protein (Bax), another member of the Bcl-2 family, are generally thought to be functionally redundant, only Bak is necessary and sufficient for VK2-induced cytochrome c (cyt c) release and cell death. Moreover, VK2-2,3 epoxide, an intracellular metabolite of VK2, was shown to covalently bind to the cysteine-166 residue of Bak. Several lines of evidence suggested that the covalent attachment of VK2 is critical for apoptosis induction. Thus this study reveals a specific role for Bak in mitochondria-mediated apoptosis. This study also provides insight into the anticancer effects of VK2 and suggests that Bak may be a potential target of cancer therapy.}, | ||
| + | author = {Karasawa, Satoki and Azuma, Motoki and Kasama, Takeshi and Sakamoto, Satoshi and Kabe, Yasuaki and Imai, Takeshi and Yamaguchi, Yuki and Miyazawa, Keisuke and Handa, Hiroshi}, | ||
| + | doi = {10.1124/mol.112.082602}, | ||
| + | issn = {1521-0111}, | ||
| + | journal = {Molecular pharmacology}, | ||
| + | keywords = {Apoptosis,Apoptosis: drug effects,Cell Death,Cell Death: drug effects,Cell Line, Tumor,Cysteine,Cysteine: metabolism,Cytochromes c,Cytochromes c: metabolism,HL-60 Cells,HeLa Cells,Humans,Mitochondria,Mitochondria: drug effects,Mitochondria: metabolism,Proto-Oncogene Proteins c-bcl-2,Proto-Oncogene Proteins c-bcl-2: metabolism,Vitamin K 2,Vitamin K 2: metabolism,Vitamin K 2: pharmacology,bcl-2 Homologous Antagonist-Killer Protein,bcl-2 Homologous Antagonist-Killer Protein: metabo}, | ||
| + | mendeley-groups = {kvitamin}, | ||
| + | month = mar, | ||
| + | number = {3}, | ||
| + | pages = {613--20}, | ||
| + | pmid = {23229512}, | ||
| + | title = {{Vitamin K2 covalently binds to Bak and induces Bak-mediated apoptosis.}}, | ||
| + | url = {http://www.ncbi.nlm.nih.gov/pubmed/23229512}, | ||
| + | volume = {83}, | ||
| + | year = {2013} | ||
| + | } | ||
| + | </bibtex> | ||
| + | |||
| + | |||
| + | [4] | ||
| + | <bibtex> | ||
| + | @article{Wang2013, | ||
| + | abstract = {Ubiquinone (UQ), a.k.a. coenzyme Q, is a redox-active lipid that participates in several cellular processes, in particular mitochondrial electron transport. Primary UQ deficiency is a rare but severely debilitating condition. Mclk1 (a.k.a. Coq7) encodes a conserved mitochondrial enzyme that is necessary for UQ biosynthesis. We engineered conditional Mclk1 knockout models to study pathogenic effects of UQ deficiency and to assess potential therapeutic agents for the treatment of UQ deficiencies. We found that Mclk1 knockout cells are viable in the total absence of UQ. The UQ biosynthetic precursor DMQ9 accumulates in these cells and can sustain mitochondrial respiration, albeit inefficiently. We demonstrated that efficient rescue of the respiratory deficiency in UQ-deficient cells by UQ analogues is side chain length dependent, and that classical UQ analogues with alkyl side chains such as idebenone and decylUQ are inefficient in comparison with analogues with isoprenoid side chains. Furthermore, Vitamin K2, which has an isoprenoid side chain, and has been proposed to be a mitochondrial electron carrier, had no efficacy on UQ-deficient mouse cells. In our model with liver-specific loss of Mclk1, a large depletion of UQ in hepatocytes caused only a mild impairment of respiratory chain function and no gross abnormalities. In conjunction with previous findings, this surprisingly small effect of UQ depletion indicates a nonlinear dependence of mitochondrial respiratory capacity on UQ content. With this model, we also showed that diet-derived UQ10 is able to functionally rescue the electron transport deficit due to severe endogenous UQ deficiency in the liver, an organ capable of absorbing exogenous UQ.}, | ||
| + | author = {Wang, Ying and Hekimi, Siegfried}, | ||
| + | doi = {10.1093/hmg/ddt330}, | ||
| + | file = {:C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wang, Hekimi - 2013 - Mitochondrial respiration without ubiquinone biosynthesis.pdf:pdf}, | ||
| + | issn = {1460-2083}, | ||
| + | journal = {Human molecular genetics}, | ||
| + | keywords = {Alleles,Animals,Ataxia,Ataxia: diet therapy,Ataxia: metabolism,Ataxia: pathology,Cell Respiration,Cell Respiration: genetics,Cell Respiration: physiology,Cell Survival,Disease Models, Animal,Electron Transport,Liver,Liver: metabolism,Membrane Proteins,Membrane Proteins: genetics,Membrane Proteins: metabolism,Mice,Mice, Knockout,Mitochondria,Mitochondria: metabolism,Mitochondrial Diseases,Mitochondrial Diseases: diet therapy,Mitochondrial Diseases: metabolism,Mitochondrial Diseases: pathology,Mitochondrial Proteins,Mitochondrial Proteins: genetics,Mitochondrial Proteins: metabolism,Muscle Weakness,Muscle Weakness: diet therapy,Muscle Weakness: metabolism,Muscle Weakness: pathology,Oxygen Consumption,Ubiquinone,Ubiquinone: analogs \& derivatives,Ubiquinone: biosynthesis,Ubiquinone: deficiency,Ubiquinone: metabolism,Ubiquinone: pharmacology,Ubiquinone: physiology,Vitamin K 2,Vitamin K 2: pharmacology}, | ||
| + | mendeley-groups = {kvitamin}, | ||
| + | month = dec, | ||
| + | number = {23}, | ||
| + | pages = {4768--83}, | ||
| + | pmid = {23847050}, | ||
| + | title = {{Mitochondrial respiration without ubiquinone biosynthesis.}}, | ||
| + | url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3888124\&tool=pmcentrez\&rendertype=abstract}, | ||
| + | volume = {22}, | ||
| + | year = {2013} | ||
| + | } | ||
| + | </bibtex> | ||
