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The most well-known and commonly used inhibitor of the MCU is [https://en.wikipedia.org/wiki/Ruthenium_red ruthenium red] (RuRed).<ref name="Woods"/> RuRed is a trinuclear, oxo-bridged complex that effectively inhibits calcium uptake without affecting mitochondrial respiration or calcium efflux.<ref name="Woods"/> The disadvantage of ruthenium red is its challenging purification.<ref name="Woods"/> Interestingly, an impure version of RuRed, termed [https://en.wikipedia.org/wiki/Ru360 Ru360], was found to be the active component of RuRed and thus another good inhibitor of the MCU.<ref name="Woods"/> Ru360 is a binuclear, oxo-bridged complex with a similar structure to that of RuRed.<ref name="Woods"/> The only flaw with Ru360 was that it showed low cell permeability, so Ru265 was developed and had twice the cell permeability of Ru360.<ref name="Woods"/> Ru265 possesses two bridged Ru centers bridged by a nitride ligand.<ref name="Woods"/> | The most well-known and commonly used inhibitor of the MCU is [https://en.wikipedia.org/wiki/Ruthenium_red ruthenium red] (RuRed).<ref name="Woods"/> RuRed is a trinuclear, oxo-bridged complex that effectively inhibits calcium uptake without affecting mitochondrial respiration or calcium efflux.<ref name="Woods"/> The disadvantage of ruthenium red is its challenging purification.<ref name="Woods"/> Interestingly, an impure version of RuRed, termed [https://en.wikipedia.org/wiki/Ru360 Ru360], was found to be the active component of RuRed and thus another good inhibitor of the MCU.<ref name="Woods"/> Ru360 is a binuclear, oxo-bridged complex with a similar structure to that of RuRed.<ref name="Woods"/> The only flaw with Ru360 was that it showed low cell permeability, so Ru265 was developed and had twice the cell permeability of Ru360.<ref name="Woods"/> Ru265 possesses two bridged Ru centers bridged by a nitride ligand.<ref name="Woods"/> | ||
- | Recent experiments suggest that Ru360 inhibits calcium uptake through interactions with the WDXXEP motif.<ref name="Woods"/> However, not much is actually known about the method of inhibition. Mutations of Asp261 and Ser259 in human MCU | + | Recent experiments suggest that Ru360 inhibits calcium uptake through interactions with the WDXXEP motif.<ref name="Woods"/> However, not much is actually known about the method of inhibition. Mutations of Asp261 and Ser259 in human MCU were shown to maintain calcium uptake into the matrix, but reduce the inhibitory effect of Ru360.<ref name="Woods"/> Curiously, the same Ser259 mutation did not affect inhibition of Ru265.<ref name="Woods"/> Additionally, a mutation in a cysteine residue in the NTD reduced the inhibitory effects of Ru265, but not Ru360.<ref name="Woods"/> So, while various inhibitors for the MCU are known, the mechanism of each is still largely unknown. |
==Medical Relevance== | ==Medical Relevance== | ||
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===Diabetes=== | ===Diabetes=== | ||
- | Calcium homeostasis dysregulation has also been proven to be instrumental in [https://en.wikipedia.org/wiki/Obesity obesity], [https://en.wikipedia.org/wiki/Insulin_resistance insulin resistance], and [https://en.wikipedia.org/wiki/Type_2_diabetes type-II diabetes].<ref name="Wang"/> The intracellular calcium concentrations in primary [https://en.wikipedia.org/wiki/Adipocyte adipocytes] from obese human subjects | + | Calcium homeostasis dysregulation has also been proven to be instrumental in [https://en.wikipedia.org/wiki/Obesity obesity], [https://en.wikipedia.org/wiki/Insulin_resistance insulin resistance], and [https://en.wikipedia.org/wiki/Type_2_diabetes type-II diabetes].<ref name="Wang"/> The intracellular calcium concentrations in primary [https://en.wikipedia.org/wiki/Adipocyte adipocytes] from obese human subjects has been found to be elevated.<ref name="Wang"/> Any inhbition of downstream calcium signaling could decrease movement of the [http://proteopedia.org/wiki/index.php/GLUT4 GLUT4] glucose transporter and glucose uptake.<ref name="Wang"/> Additionally, [https://en.wikipedia.org/wiki/Ablation ablation] of MCU in [https://en.wikipedia.org/wiki/Beta_cell β-cells] in the [https://en.wikipedia.org/wiki/Pancreas pancreas] demonstrated a decrease in cellular ATP concentration following glucose stimulation which resulted in decreased glucose-stimulated insulin secretion.<ref name="Wang"/> Furthermore, MAMs have been shown to cause glucose intolerance and mitochondrial dysfunction in primary [https://en.wikipedia.org/wiki/Hepatocyte hepatocytes] in mice.<ref name="Wang"/> Subsequent reinforcement of these MAMs has been shown to increase insulin sensitivity and glucose homeostasis.<ref name="Wang"/> |
</StructureSection> | </StructureSection> |
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This Sandbox is Reserved from Jan 13 through September 1, 2020 for use in the course CH462 Biochemistry II taught by R. Jeremy Johnson at the Butler University, Indianapolis, USA. This reservation includes Sandbox Reserved 1598 through Sandbox Reserved 1627. |
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Mitochondrial Calcium Uniporter (MCU) Complex
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References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 Baradaran R, Wang C, Siliciano AF, Long SB. Cryo-EM structures of fungal and metazoan mitochondrial calcium uniporters. Nature. 2018 Jul 11. pii: 10.1038/s41586-018-0331-8. doi:, 10.1038/s41586-018-0331-8. PMID:29995857 doi:http://dx.doi.org/10.1038/s41586-018-0331-8
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 Woods JJ, Wilson JJ. Inhibitors of the mitochondrial calcium uniporter for the treatment of disease. Curr Opin Chem Biol. 2019 Dec 20;55:9-18. doi: 10.1016/j.cbpa.2019.11.006. PMID:31869674 doi:http://dx.doi.org/10.1016/j.cbpa.2019.11.006
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Giorgi C, Marchi S, Pinton P. The machineries, regulation and cellular functions of mitochondrial calcium. Nat Rev Mol Cell Biol. 2018 Nov;19(11):713-730. doi: 10.1038/s41580-018-0052-8. PMID:30143745 doi:http://dx.doi.org/10.1038/s41580-018-0052-8
- ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 Wang CH, Wei YH. Role of mitochondrial dysfunction and dysregulation of Ca(2+) homeostasis in the pathophysiology of insulin resistance and type 2 diabetes. J Biomed Sci. 2017 Sep 7;24(1):70. doi: 10.1186/s12929-017-0375-3. PMID:28882140 doi:http://dx.doi.org/10.1186/s12929-017-0375-3
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 Fan C, Fan M, Orlando BJ, Fastman NM, Zhang J, Xu Y, Chambers MG, Xu X, Perry K, Liao M, Feng L. X-ray and cryo-EM structures of the mitochondrial calcium uniporter. Nature. 2018 Jul 11. pii: 10.1038/s41586-018-0330-9. doi:, 10.1038/s41586-018-0330-9. PMID:29995856 doi:http://dx.doi.org/10.1038/s41586-018-0330-9
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