Two gatekeepers for 1 gate: Research has implications for diabetes, stroke, cancer, and age-related neurological diseases
A decades-long mystery of how the cell's powerhouse, and its energy currency of calcium ion flow, is maintained under different physiological conditions has been solved by researchers from the Perelman School of Medicine at the University of Pennsylvania.
The team, led by Kevin Foskett, PhD, chair of the department of Physiology, 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 findings, reported early online this month in Cell Reports, add important new insights into the gatekeeping mechanism of calcium entry into the cell power unit, called the mitochondria, and may help scientists better understand and target newly identified molecular components that regulate calcium flux.
"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," Foskett said. 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. Disorders of mitochondria can disrupt energy production, essentially like an electrical brown out or black out.
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.
Horia Vais, PhD, a senior research investigator in the Foskett lab measured calcium ion currents flowing through the MCU. He 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. In 2012, the Foskett group and Temple University collaborators established in a seminal study published in Cell that the mitochondrial protein MICU1 is required to set the proper level of calcium uptake under normal conditions. However, 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. "We now know that this important ion channel gateway deep inside the cell is regulated by two gatekeepers, governed by EMRE," Foskett said.
"Our study unravels the mystery of the mitochondrial gatekeeping mechanism," said co-first author Karthik Mallilankaraman, PhD, a postdoctoral fellow in the Foskett lab who is now an assistant professor of Physiology at the National University of Singapore. "We 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."
Other authors, all from the Foskett lab, are Daniel Mak, Henry Hoff, Riley Payne, and Jessica Tanis. This work was supported by the National Institute of General Medical Sciences (GM56328).
Karen Kreeger | EurekAlert!
Unique brain 'fingerprint' can predict drug effectiveness
11.07.2018 | McGill University
Direct conversion of non-neuronal cells into nerve cells
03.07.2018 | Universitätsmedizin der Johannes Gutenberg-Universität Mainz
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
16.07.2018 | Physics and Astronomy
16.07.2018 | Transportation and Logistics
16.07.2018 | Agricultural and Forestry Science