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 Show me your leaves - Health check for urban trees
12.12.2017 | Gesellschaft für Ökologie e.V.

nachricht Liver Cancer: Lipid Synthesis Promotes Tumor Formation
12.12.2017 | 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: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

Im Focus: Successful Mechanical Testing of Nanowires

With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong

Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Long-lived storage of a photonic qubit for worldwide teleportation

12.12.2017 | Physics and Astronomy

Multi-year submarine-canyon study challenges textbook theories about turbidity currents

12.12.2017 | Earth Sciences

Electromagnetic water cloak eliminates drag and wake

12.12.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>