Mitochondria are spherical or rod-shaped organelles found within the cytoplasm of eukaryotic cells, referred to as the powerhouse of the cell as they act as the site for the production of high-energy compounds which are vital energy source for several cellular processes. Calcium handling by mitochondria is a key feature in cell life. It is involved in energy production for cell activity, in buffering and shaping cytosolic calcium rises and also in determining cell fate by triggering or preventing apoptosis, or cell-death.
Both mitochondria and the mechanisms involved in the control of calcium homeostasis have been extensively studied, however, they still provide researchers with challenges. Now a decades-long mystery of how mitochondria’s energy currency of calcium ion flow is maintained under different physiological conditions has been solved by researchers from the University of Pennsylvania and the University of Singapore. The team state that they have identified a novel regulatory mechanism that governs levels of calcium inside cells; without this physiological mechanism, calcium levels can increase uncontrollably, contributing to a variety of neurodegenerative, metabolic, and cardiovascular diseases. The opensource study is published in the journal Cell Reports.
Previous studies show that 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. Understanding the molecular mechanisms by which mitochondrial calcium levels are regulated may have important implications for designing therapeutic targets for a variety of diseases, including diabetes, stroke, cancer, and age-related neurological diseases that have been related to mitochondrial dysfunction. The current study shows 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.
The current study measured calcium ion currents flowing through the MCU to show that this mechanism ensures that MCU activity is low, thus preventing calcium overload inside the mitochondria. Results show that this gate-keeping brake can be overcome by higher matrix calcium concentrations during cell signaling. The lab state that in 2012, they established that the mitochondrial protein MICU1 is required to set the proper level of calcium uptake under normal conditions. In contrast, data findings show that MICU1 is not localized in the matrix, rather, it is localised in the inter-membrane space.
Results show that one end of an MCU-associated membrane, called EMRE, resides in the mitochondrial matrix and contains acidic amino acids resembling calcium-sensing regions of other ion-channels. Data findings show that neutralizing these regions completely abolished calcium regulation, and the mitochondria became overloaded with calcium. From this, the group observed that EMRE-dependent matrix calcium regulation of MCU required MICU1, MICU2, and calcium on the other side of the inner membrane to work properly. They go on to state that EMRE couples calcium sensors on both sides of the inner membrane to regulate MCU activity and the extent of mitochondrial calcium flux. They conclude that it is now known this important ion-channel gateway deep inside the cell is regulated by two gatekeepers and governed by EMRE.
The team surmise that their study unravels the mystery of the mitochondrial gate-keeping mechanism. They go on to add that they have shown that mitochondria are protected from calcium overload by components on either side of the mitochondrial inner membrane, MICU proteins on one side and matrix calcium on the other, coupled by EMRE. For the future, the researchers state that their findings add important new insights into the gate-keeping mechanism of calcium entry into mitochondria, and may help the global medical community better understand and target newly identified molecular components that regulate calcium flux.