Sandbox Reserved 1601

From Proteopedia

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Revision as of 18:10, 23 March 2020

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) (Heumann Test Page)

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You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

1 Overview
2 Structure
- 2.1 Selectivity Filter
- 2.2 Common Mutations
3 Medical Relevance
4 Regulation/Inhibition

Overview

Reference practice ^[3]

Structure

Selectivity Filter

Common Mutations

Medical Relevance

A number of medical conditions all over the body are caused by disruption of the homeostasis of mitochondrial calcium. Diabetes, heart failure, and cancer are just a few members of this broad group of conditions.

Diabetes

In healthy individuals, the 𝛽-cells in the pancreas are responsible for sensing the concentration of glucose in the bloodstream and releasing the appropriate amount of insulin in response. While the mechanism of this activation isn't entirely understood, we can explain a large portion of it in the context of mitochondrial calcium homeostasis. Increased concentration of glucose causes glycolysis in the cell, which increases the amount of ATP. This increase of ATP closes potassium channels in the membrane of the 𝛽-cell which causes depolarization of the membrane. When a certain threshold potential is reached, calcium channels open and create microdomains of calcium below the plasma membrane which allows insulin release by activatin PKC 𝛽-type II. Furthermore, there is a pool of mitochondria in 𝛽-cells near the calcium channels which take in the calcium through the MCU. The mitochondria then create more ATP which sustains and amplifies insulin secretion ^[4].

Any defect in the MCU affects the homeostasis of calcium in the mitochondria. In this case, it can cause insulin secretion to be diminished which can be a causal factor for diabetes I and II.

Heart Failure

Cancer

Regulation/Inhibition

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References

^[3]

^[5]

^[4]

^[6]

^[7]

↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
↑ ^3.0 ^3.1 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
↑ ^4.0 ^4.1 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
↑ 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
↑ Kamer KJ, Jiang W, Kaushik VK, Mootha VK, Grabarek Z. Crystal structure of MICU2 and comparison with MICU1 reveal insights into the uniporter gating mechanism. Proc Natl Acad Sci U S A. 2019 Feb 12. pii: 1817759116. doi:, 10.1073/pnas.1817759116. PMID:30755530 doi:http://dx.doi.org/10.1073/pnas.1817759116
↑ 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

Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_1601"

@@ Line 21: / Line 21: @@
 === Diabetes ===
-In healthy individuals, the 𝛽-cells in the pancreas are responsible for sensing the concentration of glucose in the bloodstream and releasing the appropriate amount of insulin in response. While the mechanism of this activation isn't entirely understood, we can explain a large portion of it in the context of mitochondrial calcium homeostasis.  Increased concentration of glucose causes glycolysis in the cell, which increases the amount of ATP.  This increase of ATP closes potassium channels in the membrane of the 𝛽-cell which causes depolarization of the membrane.  When a certain threshold potential is reached, calcium channels open and create microdomains of calcium below the plasma membrane which allows insulin release by activatin PKC 𝛽-type II.  Furthermore, there is a pool of mitochondria in 𝛽-cells near the calcium channels which take in the calcium through the MCU.  The mitochondria then create more ATP which sustains and amplifies insulin secretion.
+In healthy individuals, the 𝛽-cells in the pancreas are responsible for sensing the concentration of glucose in the bloodstream and releasing the appropriate amount of insulin in response. While the mechanism of this activation isn't entirely understood, we can explain a large portion of it in the context of mitochondrial calcium homeostasis.  Increased concentration of glucose causes glycolysis in the cell, which increases the amount of ATP.  This increase of ATP closes potassium channels in the membrane of the 𝛽-cell which causes depolarization of the membrane.  When a certain threshold potential is reached, calcium channels open and create microdomains of calcium below the plasma membrane which allows insulin release by activatin PKC 𝛽-type II.  Furthermore, there is a pool of mitochondria in 𝛽-cells near the calcium channels which take in the calcium through the MCU.  The mitochondria then create more ATP which sustains and amplifies insulin secretion <ref name="Woods" />.
 Any defect in the MCU affects the homeostasis of calcium in the mitochondria.  In this case, it can cause insulin secretion to be diminished which can be a causal factor for diabetes I and II.