Featured Research

from universities, journals, and other organizations

What keeps a cell's energy source going?

Date:
November 27, 2012
Source:
Perelman School of Medicine at the University of Pennsylvania
Summary:
Most healthy cells rely on a complicated process to produce the fuel ATP. Knowing how ATP is produced by the cell’s energy storehouse – the mitochondria -- is important for understanding a cell’s normal state, as well as what happens when things go wrong, for example in cancer, cardiovascular disease, neurodegeneration, and many rare disorders of the mitochondria.

Ca2+ flux across the inner mitochondrial membrane regulates cell bioenergetics, cytoplasmic Ca2+ signals and activation of cell death pathways. Ca2+ uptake from the cytoplasm is driven by the electrochemical gradient generated during ATP production, mediated by a Ca2+ ion channel called the mitochondrial Ca2+ uniporter. Molecular components of the uniporter include MCU, the Ca2+ conducting pore, and MICU1, a MCU regulator that limits Ca2+ permeation through MCU at rest. MCUR1 is as an essential third component of the uniporter complex. In the absence of MCUR1, mitochondrial Ca2+ uptake is markedly reduced, with adverse cellular consequences, including compromised cellular bioenergetics, diminished oxidative phosphorylation and activation of autophagy. The cover shows mitochondria (green) stained with the mitochondrial membrane potential indicator, rhodamine 123 in living primary mouse embryonic fibroblasts. Nuclei are stained with DAPI (blue).
Credit: Lili Guo, Perelman School of Medicine, University of Pennsylvania

Most healthy cells rely on a complicated process to produce the fuel ATP. Knowing how ATP is produced by the cell's energy storehouse -- the mitochondria -- is important for understanding a cell's normal state, as well as what happens when things go wrong, for example in cancer, cardiovascular disease, neurodegeneration, and many rare disorders of the mitochondria.

Two years ago, Kevin Foskett, PhD, professor of Physiology at the Perelman School of Medicine, University of Pennsylvania, and colleagues discovered that fundamental control of ATP production is an ongoing shuttle of calcium to the mitochondria from another cell compartment. They found that mitochondria rely on this transfer to make enough ATP to support normal cell metabolism.

Foskett's lab and the lab of colleague Muniswamy Madesh, PhD, at Temple University, discovered last month an essential mechanism that regulates the flow of calcium into mitochondria, described in the October 26 issue of Cell. They found that the mitochondrial protein MICU1 is required to establish the proper level of calcium uptake under normal conditions.

In a new paper out this week in Nature Cell Biology, the same Penn-Temple team describe a new protein and its function. Like MICU1, this new protein, MCUR1, interacts physically with MCU, the uniporter calcium ion channel within the mitochondria. Calcium uptake is driven by a voltage across the inner mitochondrial membrane and mediated by the calcium-selective ion channel called the uniporter.

"But this newly described protein, MCUR1, has the opposite role as MICU1," notes Foskett. "It seems to be a subunit that, together with MCU, is required for a functional uniporter calcium channel."

Many cell plasma membrane ion channels also have subunits that are required for those channels to work. Before this paper, there was no realization that this mitochondrial channel, MCU, did as well.

Maintaining the correct levels of calcium in the mitochondria plays an important role in cellular physiology: Calcium flux across the inner mitochondrial membrane regulates cell energy production and activation of cell-death pathways, for example. In MICU1's absence mitochondria become overloaded with calcium, generating excessive amounts of reactive oxygen molecules and eventually cell death. In contrast, in the absence of MCUR1, mitochondria cannot take up enough calcium. This also has detrimental effects: the cells cannot make enough ATP and they activate autophagy, a mechanism in which cells "eat themselves" to provide sufficient nutrients for survival.

Both papers deal with the function of the uniporter, the calcium channel in the inner membrane of mitochondria that lets calcium get into the mitochondrial matrix where it can do good things like promote ATP synthesis and healthy bioenergetics, or bad things, like mitochondrial-mediated cell death, apoptosis and necrosis.

Because of these two papers, the uniporter is now recognized as a channel complex, containing -- at least -- MCU, MCUR1 and MICU1. Since the uniporter can be a therapeutic target is reperfusion injury, ischemic injury, and programmed cell death, MCUR1 and its interaction with MCU are now targets for drug development.

Other investigators contributing to the work include Cesar Cardenas, Jun Yang, Marioly Muller, Russell Miller, Jill E. Kolesar, Brett Kaufman, all from Penn; first author Karthik Mallilankaraman, Patrick Doonan, Harish C. Chandramoorthy, Krishna M. Irrinki, and Priyanka Madireddi, all from Temple; Tunde Golenar, Gyorgy Csordas, Gyorgy Hajnoczky, all from Thomas Jefferson University; and Jordi Molgo, Institute de Neurobiologie Alfred Fessard, Laboratoire de Neurobiolgie Cellulaire et Développement, France.

The research was supported by funding from the National Heart, Lung, and Blood Institute and National Institute of General Medical Sciences grants R01 HL086699, HL086699-01A2S1, 1S10RR027327-01, GM56328 and the American Heart Association.


Story Source:

The above story is based on materials provided by Perelman School of Medicine at the University of Pennsylvania. Note: Materials may be edited for content and length.


Journal References:

  1. Karthik Mallilankaraman, César Cárdenas, Patrick J. Doonan, Harish C. Chandramoorthy, Krishna M. Irrinki, Tünde Golenár, György Csordás, Priyanka Madireddi, Jun Yang, Marioly Müller, Russell Miller, Jill E. Kolesar, Jordi Molgó, Brett Kaufman, György Hajnóczky, J. Kevin Foskett, Muniswamy Madesh. MCUR1 is an essential component of mitochondrial Ca2 uptake that regulates cellular metabolism. Nature Cell Biology, 2012; DOI: 10.1038/ncb2622
  2. Karthik Mallilankaraman, Patrick Doonan, César Cárdenas, Harish C. Chandramoorthy, Marioly Müller, Russell Miller, Nicholas E. Hoffman, Rajesh Kumar Gandhirajan, Jordi Molgó, Morris J. Birnbaum, Brad S. Rothberg, Don-On Daniel Mak, J. Kevin Foskett, Muniswamy Madesh. MICU1 Is an Essential Gatekeeper for MCU-Mediated Mitochondrial Ca2 Uptake that Regulates Cell Survival. Cell, 2012; 151 (3): 630 DOI: 10.1016/j.cell.2012.10.011

Cite This Page:

Perelman School of Medicine at the University of Pennsylvania. "What keeps a cell's energy source going?." ScienceDaily. ScienceDaily, 27 November 2012. <www.sciencedaily.com/releases/2012/11/121127130025.htm>.
Perelman School of Medicine at the University of Pennsylvania. (2012, November 27). What keeps a cell's energy source going?. ScienceDaily. Retrieved July 29, 2014 from www.sciencedaily.com/releases/2012/11/121127130025.htm
Perelman School of Medicine at the University of Pennsylvania. "What keeps a cell's energy source going?." ScienceDaily. www.sciencedaily.com/releases/2012/11/121127130025.htm (accessed July 29, 2014).

Share This




More Health & Medicine News

Tuesday, July 29, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Generics Eat Into Pfizer's Sales

Generics Eat Into Pfizer's Sales

Reuters - Business Video Online (July 29, 2014) — Pfizer, the world's largest drug maker, cut full-year revenue forecasts because generics could cut into sales of its anti-arthritis drug, Celebrex. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Nigeria Ups Ebola Stakes on 1st Death

Nigeria Ups Ebola Stakes on 1st Death

Reuters - Business Video Online (July 29, 2014) — Nigerian authorities have shut and quarantined a Lagos hospital where a Liberian man died of the Ebola virus, the first recorded case of the highly-infectious disease in Africa's most populous economy. David Pollard reports Video provided by Reuters
Powered by NewsLook.com
Running 5 Minutes A Day Might Add Years To Your Life

Running 5 Minutes A Day Might Add Years To Your Life

Newsy (July 29, 2014) — According to a new study, just five minutes of running or jogging a day could add years to your life. Video provided by Newsy
Powered by NewsLook.com
Ebola Outbreak Poses Little Threat To U.S.: CDC

Ebola Outbreak Poses Little Threat To U.S.: CDC

Newsy (July 29, 2014) — The Ebola outbreak in West Africa poses little threat to Americans, according to officials with the Centers for Disease Control and Prevention. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins