The mitochondrial calcium uniporter (MCU) is a

transmembrane protein A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

that allows the passage of

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...

ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

s from a cell's

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

into

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

. Its activity is regulated by MICU1 and MICU2, which together with the MCU make up the mitochondrial calcium uniporter complex. The MCU is one of the primary sources of mitochondria uptake of calcium, and flow is dependent on

membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...

of the

inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...

and the concentration of calcium in the cytosol relative to the concentration in the mitochondria. Balancing calcium concentration is necessary to increase the cell's energy supply and regulate cell death. Calcium is balanced through the MCU in conjunction with the

sodium-calcium exchanger The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by al ...

. The MCU has a very low

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for calcium, so the cytosolic calcium concentration needs to be approximately 5-10 uM for significant transport of calcium into the mitochondria. Mitochondria are closely associated with the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

(ER), at contact sites, which contains stores of cellular calcium ions for

calcium signaling Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts all ...

. The presence of 1,4,5-triphosphate (IP₃) triggers the release of calcium from these intracellular stores, which creates microdomains of high calcium concentration between the ER and the mitochondria, creating the conditions for the MCU to take up calcium.

Ruthenium red The inorganic dye ammoniated ruthenium oxychloride, also known as ruthenium red, is used in histology to stain aldehyde fixed mucopolysaccharides. Ruthenium red (RR) has also been used as a pharmacological tool to study specific cellular mechani ...

and

Ru360 Ru360 is an oxo-bridged dinuclear ruthenium ammine complex with an absorption spectrum maximum at 360 nm. It is an analog of ruthenium red, a well-known effective inhibitor of the mitochondrial calcium uniporter. Ru360 was discovered afte ...

are typical reagents used to experimentally block the MCU to study its properties and role in mitochondrial signaling.

MICU1 and MICU2

MICU1

The mitochondrial calcium uptake 1 (MICU1) is a single pass membrane protein, it contains 2 binding domains. This protein was first discovered before the MCU by only a few months. MICU1 was used as a bait to figure out what the core of the mitochondrial calcium uniporter was. Once both MICU1 and MCU were discovered scientists made some intriguing discoveries in regards to the two proteins. Both MICU1 and MCU share similar RNA sequences, same pattern of expression, and they both interact with one another in the intermitochondrial membrane. It was first found through the use of siRNA screening of the membrane. The functions of MICU1 are still being studied; however, there are some important functions MICU1 plays in the intermitochondrial membrane. MICU1 helps to stabilize the entire mitochondrial calcium uniporter complex, it also limits the amount of calcium that enters the cell during low concentrations of calcium. However, along with limiting the entry of calcium into the mitochondrial matrix, it functions alongside MCU to keep the accumulated calcium inside the matrix of the mitochondria, and promotes ion specificity by preventing aberrant loading of transition metals into the mitochondria.

MICU2

Mitochondrial calcium uptake 2 (MICU2) is another intermitochondrial membrane protein. It works alongside MICU1 and contains roughly 25% of the same DNA sequence. MICU2 works with MICU1 and MCU to reduce the amount of calcium coming into the matrix. It is shown that when both MICU1 and MICU2 are sequestered there is reduced calcium; however, whenever MICU1 is sequestered and MICU2 is activated, normal calcium flow. It is also shown that all three, MCU, MICU1, and MICU2 are part of a single complex, the mitochondrial calcium uniporter complex resumes. Research using a CRISPR/Cas9 technique has found that MICU1 and MICU2 play other roles as well. They are essential for cell growth, cell invasion, and cell replication.

References

{{Reflist Transmembrane transporters Calcium signaling Mitochondria