Maintaining calcium balance by mitochondria

Maintaining calcium balance by mitochondria

Mitochondria are comprised of two membranes. The outer membrane covers this cell component like a skin, and the inner membrane folds over many times, creating layers to increase surface area for the chemical reactions that produce the body's energy molecules. 

Calcium is an important chemical messenger that regulates a variety of cellular processes. When calcium levels rise in the cell's interior during cell signaling, mitochondria rapidly take it in through a protein complex called the mitochondrial calcium uniporter (MCU). The MCU is an ion channel that governs uptake of calcium ions. Maintaining correct levels of calcium in and outside of the mitochondria is important because it is required for cellular energy production but an overload can lead to cell death.

Researchers measured calcium ion currents flowing through the MCU. They discovered that the concentration of calcium inside the mitochondria matrix strongly regulates the activity of MCU. The matrix contains enzymes, strands of DNA, protein crystals, glycogen, and lipid and occupies the inner space inside the mitochondria.

This mechanism ensures that MCU activity is low, preventing calcium overload inside the mitochondria. This gatekeeping brake can be overcome by higher matrix calcium concentrations during cell signaling.  The current study showed that MICU1 is not localized in the matrix, but in the inter-membrane space.

The authors established that one end of an MCU-associated membrane, called EMRE, resided in the mitochondrial matrix and contained acidic amino acids resembling calcium-sensing regions of other ion channels. Neutralizing these regions completely abolished calcium regulation, and the mitochondria became overloaded with calcium.

From this, the team found that EMRE-dependent matrix calcium regulation of MCU required MICU1, MICU2, and calcium on the other side of the inner membrane to work properly. EMRE couples calcium sensors on both sides of the inner membrane to regulate MCU activity and the extent of mitochondrial calcium flux. "Our study unravels the mystery of the mitochondrial gatekeeping mechanism," said co-first author.