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Overview
Calcium ions are universal and versatile signaling molecules. Their functions include muscle contraction, neuron excitability, and cell growth. Mitochondria regulate and decode calcium inputs that are necessary for many functions. Mitochondrial calcium regulates mitochondrial metabolism and has an impact in apoptosis, which will be talked about in greater depths later. This is important due to the fact an uncontrolled increase of calcium in the cytoplasm or prolonged presence of calcium in the mitochondria leads to apoptosis[3]. The history behind the MCU came from the idea that individual mitochondria could take up high levels of calcium using ATP-derived energy founded in the 1960s.At resting conditions, the concentration of calcium in the mitochondria is around the same as in the cytoplasm (100-200 nM), but it can accumulate up to 10-20x that amount when stimulated. Calcium uptake into the mitochondrial matrix is driven by the membrane potential created by the electron transport chain. The calcium can flow through the outer membrane with ease as it is highly permeable, due to the pores formed by voltage-dependent anion-selective channel proteins. Now for the calcium pass through the inner membrane the MCU is needed. There are other pathways for calcium to get through the inner membrane but MCU is by far the most dominant. [4]
Structure
The precise identity of the MCU as the major calcium transporter remained elusive until 2011. Thanks to a series of combined efforts involving NMR spectroscopy, cry-EM, and x-ray crystallography they were able to see the structure of the membrane-bound transporter and its regulatory machinery. [3] The actual MCU complex is a tetrameric dimer of dimers assembly. As show in the 3D image to the right. What the 3D image does not sure is MICU1 and MICU 2, which are tight regulators off the MCU-mediated calcium uptake that actual bring in the calcium and move it towards the selectivity filter in the main MCU complex. There are three other proteins in the complete complex. EMRE, MCUb, and MCUR1. The EMRE is what associates MICU1 and MICU2 with main MCU protein.
Selectivity Filter
The pore-forming subunit of the MCU contains 351 amino acid residues with both the N- and C-terminal domains located in the matrix of the mitochondria. The two transmembrane domains, TM1 and TM2, are connected by a solvent- exposed loop with a highly conserved DXXE motif, which is essential for the calcium transport, located in the upper helix of TM2
Common Mutations
Medical Relevance
Diabetes
Cancer
Alzheimer's
Other
Regulation/Inhibition
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