Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Penn study solves mystery of cell powerhouse's balance of calcium


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 mitochondrial matric calcium ion concentration regulates activity of the major mitochondrial calcium influx pathway, as measured by patch clamp physiology.

Credit: The lab of Kevin Foskett, PhD, Perelman School of Medicine, 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!

More articles from Health and Medicine:

nachricht Advanced analysis of brain structure shape may track progression to Alzheimer's disease
26.10.2016 | Massachusetts General Hospital

nachricht Indian roadside refuse fires produce toxic rainbow
26.10.2016 | Duke University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Etching Microstructures with Lasers

Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.

This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...

Im Focus: Light-driven atomic rotations excite magnetic waves

Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion

Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

VDI presents International Bionic Award of the Schauenburg Foundation

26.10.2016 | Awards Funding

3-D-printed magnets

26.10.2016 | Power and Electrical Engineering

Advanced analysis of brain structure shape may track progression to Alzheimer's disease

26.10.2016 | Health and Medicine

More VideoLinks >>>