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 NIH scientists describe potential antibody treatment for multidrug-resistant K. pneumoniae
14.03.2018 | NIH/National Institute of Allergy and Infectious Diseases

nachricht Researchers identify key step in viral replication
13.03.2018 | University of Pittsburgh Schools of the Health Sciences

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: Locomotion control with photopigments

Researchers from Göttingen University discover additional function of opsins

Animal photoreceptors capture light with photopigments. Researchers from the University of Göttingen have now discovered that these photopigments fulfill an...

Im Focus: Surveying the Arctic: Tracking down carbon particles

Researchers embark on aerial campaign over Northeast Greenland

On 15 March, the AWI research aeroplane Polar 5 will depart for Greenland. Concentrating on the furthest northeast region of the island, an international team...

Im Focus: Unique Insights into the Antarctic Ice Shelf System

Data collected on ocean-ice interactions in the little-researched regions of the far south

The world’s second-largest ice shelf was the destination for a Polarstern expedition that ended in Punta Arenas, Chile on 14th March 2018. Oceanographers from...

Im Focus: ILA 2018: Laser alternative to hexavalent chromium coating

At the 2018 ILA Berlin Air Show from April 25–29, the Fraunhofer Institute for Laser Technology ILT is showcasing extreme high-speed Laser Material Deposition (EHLA): A video documents how for metal components that are highly loaded, EHLA has already proved itself as an alternative to hard chrome plating, which is now allowed only under special conditions.

When the EU restricted the use of hexavalent chromium compounds to special applications requiring authorization, the move prompted a rethink in the surface...

Im Focus: Radar for navigation support from autonomous flying drones

At the ILA Berlin, hall 4, booth 202, Fraunhofer FHR will present two radar sensors for navigation support of drones. The sensors are valuable components in the implementation of autonomous flying drones: they function as obstacle detectors to prevent collisions. Radar sensors also operate reliably in restricted visibility, e.g. in foggy or dusty conditions. Due to their ability to measure distances with high precision, the radar sensors can also be used as altimeters when other sources of information such as barometers or GPS are not available or cannot operate optimally.

Drones play an increasingly important role in the area of logistics and services. Well-known logistic companies place great hope in these compact, aerial...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

Ultrafast Wireless and Chip Design at the DATE Conference in Dresden

16.03.2018 | Event News

International Tinnitus Conference of the Tinnitus Research Initiative in Regensburg

13.03.2018 | Event News

International Virtual Reality Conference “IEEE VR 2018” comes to Reutlingen, Germany

08.03.2018 | Event News

Latest News

Development and Fast Analysis of 3D Printed HF Components

19.03.2018 | Trade Fair News

In monogamous species, a compatible partner is more important than an ornamented one

19.03.2018 | Life Sciences

Signaling Pathways to the Nucleus

19.03.2018 | Life Sciences

Science & Research
Overview of more VideoLinks >>>