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

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 Universit y 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.


'"/>

Source:Johns Hopkins Medical Institutions


Related biology news :

1. Hopkins AIDS experts issue warning about global efforts to provide drug therapies
2. Hopkins scientists uncover tags that force proteins to cell surface
3. Johns Hopkins flu expert calls for mandatory vaccination of health care workers
4. Whole-genome study at Johns Hopkins reveals a new gene associated with abnormal heart rhythm
5. Hopkins study suggests commercially available antibiotic may help fight dementia in HIV patients
6. Johns Hopkins lab scientists tame overactive CF protein
7. Hopkins researchers develop new tool to watch real-time chemical activity in cells
8. Hopkins scientists show hallucinogen in mushrooms creates universal mystical experience
9. Hopkins researchers discover how brain protein might control memory
10. Hopkins scientists link immune response to ghost parasites and severely congested sinuses
11. NYU researchers simulate molecular biological clock
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:3/9/2016)... PALM BEACH GARDENS, Fla. , March 9, ... of identity management authentication and enrollment solutions, today ... proven DigitalPersona ® Altus multi-factor ... enable IT and InfoSec managers to step-up security ... friction.  Washington, DC ...
(Date:3/3/2016)... , March 3, 2016  FlexTech, a SEMI Strategic ... of Innovation, Research & Development, Leadership in Education, and, ... is the 9 th year of the FLEXI ... companies and individuals from past years . Judging ... a pre-described set of criteria, by a panel of ...
(Date:3/3/2016)... England and DE SOTO, Kansas ... , U.S.-based Stroke Detection Plus® to offer Oncimmune,s ... risk assessment and early detection of lung cancer ... large employers, unions and individuals. --> Early ... unions and individuals. --> Oncimmune, a leader ...
Breaking Biology News(10 mins):
(Date:4/28/2016)... ... 28, 2016 , ... Morris Midwest ( http://www.morrismidwest.com ), a ... at its Maple Grove, Minnesota technical center, May 11-12. The event will ... Almost 20 leading suppliers of tooling, accessories, software and other related technology will ...
(Date:4/27/2016)... ... , ... Shimadzu Scientific Instruments (SSI) will be showcasing a ... and Expo. Shimadzu’s high-performance instruments enable laboratories to test cannabis products for potency, ... by booth 1021 to learn how Shimadzu’s instruments can help improve QA/QC testing, ...
(Date:4/27/2016)... ... April 27, 2016 , ... Most consumers engage with ... recognition for secure access, voice recognition for hands-free communication, and facial recognition to ... with biometrics technology today. But if they asked Joey Pritikin, Vice President ...
(Date:4/27/2016)... RESEARCH TRIANGLE PARK, N.C. , April ... UTHR ) announced today that Martine Rothblatt , ... will provide an overview and update on the company,s ... Health Care Conference. The presentation will take ... Eastern Time, and can be accessed via a live ...
Breaking Biology Technology: