Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Hopkins researchers discover genetic switch that turns off an oxygen-poor cell’s combustion engine

09.03.2006


Finding has potential to limit toxic molecules



Johns Hopkins researchers have discovered a previously unrecognized role played by the gene HIF-1 as it helps cell survive when a lack of oxygen decreases production of an energy-rich molecule called ATP and increases production of toxic molecules. ATP supplies energy the cell needs to perform each of its many chemical reactions and tasks, and in this way acts as the "currency" for the cell’s energy economy.

A report on the work, done with mouse cells genetically altered to lack the HIF-1 gene, appears in the March 8 issue of Cell Metabolism.


A cell’s energy demands are met by two major types of sugar ( glucose) using machines similar to the two types of engines in a hybrid car. One machine, the mitochondrion, is an organelle that breaks down the glucose-using oxygen and produces ATP. The other does the same thing - albeit less efficiently - without using oxygen in a process called glycolysis.

Like the hybrid car, cells use oxygen and the internal combustion engine at higher speeds and rely on an electric engine without need for oxygen consumption at lower speeds. Cells consume glucose through its main energy-producing machine, the mitochondrion, when oxygen is ample. But like the internal combustion engine, this process generates pollutants or toxic oxygen molecules.

At lower oxygen levels, when cells are starved for oxygen - as during exertion or trauma -- the genetic switch that the Hopkins researchers found deliberately shuts off the cell’s mitochondrial combustion engine, which scientists had long - and erroneously -- believed ran down on its own due to lack of oxygen.

"The unexpected discovery is that this genetic switch actively shuts off the mitochondrion under low oxygen conditions, apparently to protect cells from mitochondrial toxic oxygen pollutants," said Chi Van Dang, M.D., Ph.D., professor of medicine, cell biology, oncology and pathology, and vice dean for research at the Johns Hopkins University School of Medicine.

Dang says the switch may be a target for cancer drugs because a cancer cell’s survival depends on it to convert glucose to lactic acid through glycolysis even in the presence of ample oxygen. Disruption of the switch by a drug may cause cancer cells to pollute themselves with toxic oxygen molecules and undergo apoptosis or cell death.

The new finding, made by Hopkins graduate student Jung-whan Kim and the Hopkins team led by Dang, showed that during oxygen deprivation, or hypoxia, the HIF-1 gene cuts the link between two ATP-making biochemical pathways: glycolysis, which makes modest amounts of ATP by breaking down the glucose without using oxygen; and the TCA cycle in the mitochondrion, which normally uses oxygen to produce large amounts of ATP by processing a byproduct of glycolysis.

The disruption of this link blocks the tendency of the mitochondrion to make toxic molecules as it struggles to produce ATP during hypoxia. These toxic molecules, called reactive oxygen species (ROS), damage molecules in the cell and even cause the cell to undergo apoptosis.

The target of HIF-1 is the conversion of pyruvate-the byproduct of glycolysis-into another molecule called acetyl co-enzyme A (acetyl CoA), according to Dang. When oxygen levels are normal, the cell produces acetyl CoA and feeds it into the TCA cycle within the mitochondrion. The mitochondrion then processes acetyl CoA using oxygen to obtain large amounts of ATP.

It was already known that during hypoxia, HIF-1 accelerates the output of ATP by glycolysis, Dang noted. But until now researchers thought that HIF-1 simply turned up glycolysis and let the mitochondrion slow down on its own and produce less ATP, he said. Because the mitochondrion runs on oxygen, it doesn’t work properly in hypoxic conditions, Dang explained. Instead, glycolysis is left to shoulder the burden of making ATP by being prodded into overdrive by HIF-1. And left to itself during hypoxia, the mitochondrion produces reactive oxygen species that threaten the life of the cell.

"But our discovery clearly shows that hypoxia doesn’t simply trigger a passive shutdown of the mitochondrion," said Dang. "Instead, HIF-1 acts as a genetic switch to actively shut down mitochondrial function and prevent the production of reactive oxygen species."

The Hopkins team demonstrated that HIF-1 shuts down the TCA cycle by preventing an enzyme called PDH from converting pyruvate made by glycolysis into acetyl CoA. Specifically, HIF-1 blocks the ability of PDH to make this conversion. HIF-1 does this by activating a protein called PDK, which binds to PDH and prevents it from performing this critical task. This starves the TCA cycle of acetyl CoA and shuts it down.

The Hopkins researchers made their discovery using mouse embryo fibroblast (MEF) cells that were genetically altered to lack HIF-1. When the investigators exposed these so-called HIF-1 null MEFs to hypoxic conditions, the cells were unable to activate PDK to block mitochondrial function. This showed that HIF-1 is required to activate PDK.

The team then genetically engineered HIF-1 null MEFs and forced PDK to work-even in the absence of the HIF-1 gene. The hypoxic cells once again accelerated glycolysis and produced increased amounts of ATP; and with the PDK forced to work, the cells were also able to shut down the TCA cycle. This showed that PDK is the protein activated by HIF-1 to prevent the mitochondrion from producing ROS.

The other authors of this paper include Jung-whan Kim, Irina Tchernyshyov and Gregg L. Semenza, who discovered HIF-1 a decade ago.

Eric Vohr | EurekAlert!
Further information:
http://www.jhmi.edu

More articles from Life Sciences:

nachricht Bare bones: Making bones transparent
27.04.2017 | California Institute of Technology

nachricht Link Discovered between Immune System, Brain Structure and Memory
26.04.2017 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

Bare bones: Making bones transparent

27.04.2017 | Life Sciences

Study offers new theoretical approach to describing non-equilibrium phase transitions

27.04.2017 | Physics and Astronomy

From volcano's slope, NASA instrument looks sky high and to the future

27.04.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>