Sandbox Reserved 1601: Difference between revisions
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Under resting conditions, the calcium concentration in the mitochondria is about the same as in the cytoplasm, but when stimulated, it can increase calcium concentration 10-20-fold.<ref name="Giorgi">PMID:30143745</ref> Mitochondria-associated ER membranes (MAMs) exist between mitochondria and the endoplasmic reticulum, the two largest cellular stores of calcium, to allow for efficient transport of calcium ions.<ref name="Wang">PMID:28882140</ref> The transfer of electrons through respiratory complexes I-IV produces the energy to pump hydrogen ions into the intermembrane space (IMS) and create the proton electrochemical gradient potential.<ref name="Giorgi"/> This negative electrochemical potential is the driving force that moves positively charged calcium ions into the mitochondrial matrix.<ref name="Giorgi"/> | Under resting conditions, the calcium concentration in the mitochondria is about the same as in the cytoplasm, but when stimulated, it can increase calcium concentration 10-20-fold.<ref name="Giorgi">PMID:30143745</ref> Mitochondria-associated ER membranes (MAMs) exist between mitochondria and the endoplasmic reticulum, the two largest cellular stores of calcium, to allow for efficient transport of calcium ions.<ref name="Wang">PMID:28882140</ref> The transfer of electrons through respiratory complexes I-IV produces the energy to pump hydrogen ions into the intermembrane space (IMS) and create the proton electrochemical gradient potential.<ref name="Giorgi"/> This negative electrochemical potential is the driving force that moves positively charged calcium ions into the mitochondrial matrix.<ref name="Giorgi"/> | ||
Regulation of the uptake and efflux of calcium is important to increase calcium levels enough to activate certain enzymes, but also avoid calcium overload and apoptosis.<ref name="Wang"/> Mitochondrial calcium increases ATP production by activating pyruvate dehydrogenase, | Regulation of the uptake and efflux of calcium is important to increase calcium levels enough to activate certain enzymes, but also avoid calcium overload and apoptosis.<ref name="Wang"/> Mitochondrial calcium increases ATP production by activating pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and isocitrate dehydrogenase in the Krebs cycle.<ref name="Wang"/> Therefore, deficiency of MCU leads to decrease of enzyme activity and of oxidative phosphorylation. | ||
==Structure== | ==Structure== | ||
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==Medical Relevance== | ==Medical Relevance== | ||
== | The MCU has a large role in disease because of its effect on apoptosis and cell signaling. The overload of the mitochondrial matrix with calcium leads to release of cytochrome c, overproduction of reactive oxygen species, mitochondrial swelling, and the opening of the mitochondrial permeability transition pore (mPTP) which all lead to apoptotic cell death.<ref name="Woods"/> This connection between mitochondrial calcium and apoptosis makes the MCU dysregulation a large contributor to cell death and disease. Calcium machinery in the mitochondria are targets for proto-oncogenes and tumor suppressors for this very reason.<ref name="Giorgi"/> Apoptosis can either be induced or repressed. Furthermore, external stimuli can activate receptors in the endoplasmic reticulum that release calcium and activate signal transductions.<ref name="Wang"/> Sequestration of calcium in the mitochondria is vital to shut down these activations, so any impact in movement of calcium ions can cause a wide variety of diseases.<ref name="Wang"/> | ||
===Neurodegenerative Disorders=== | ===Neurodegenerative Disorders=== | ||
Disruption in calcium homeostasis leads to a wide range of neurodegenerative disorders. The MCU complex has been identified to play a large role in neuromuscular disease because of a loss or mutation of MICU1.<ref name="Woods"/> This causes myopathy, learning difficulties, and progressive movement disorders which can be lethal.<ref name="Woods"/> In Alzheimer's disease, the buildup of amyloid-β plaques in the brain leads to increased calcium uptake in neurons and cell death.<ref name="Woods"/> Similarly, in early onset Parkinson's Disorder, degradation of MICU1 by the protein ligase Parkin | |||
===Diabetes=== | ===Diabetes=== | ||
