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!
NIST scientists discover how to switch liver cancer cell growth from 2-D to 3-D structures
17.11.2017 | National Institute of Standards and Technology (NIST)
High speed video recording precisely measures blood cell velocity
15.11.2017 | ITMO University
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
17.11.2017 | Physics and Astronomy
17.11.2017 | Health and Medicine
17.11.2017 | Studies and Analyses