Scientists from the Massachusetts Institute of Technology have developed a new optical sensor that can track zinc in the body's cells, enabling researchers to learn more about its functions.
Zinc is an essential mineral and is found in every tissue in the body. While the majority of zinc is tightly bound to proteins, tiny amounts are only loosely bound, or "mobile."
These mobile zinc ions are believed to be crucial for the functioning of organs, including the brain, pancreas and prostate gland.
To date, scientists do not fully understand the role zinc plays in biological systems, but the Massachusetts Institute of Technology (MIT) scientists believe their sensor could change that.
In a paper published in the Proceedings of the National Academy of Sciences, they describe how the sensor fluoresces when it binds to zinc and can be targeted to a specific organelle within a cell, enabling them to establish where the zinc is most concentrated.
The sensor relies on Zinpyr1 (ZP1), a molecule originally developed at the same MIT lab more than 10 years ago. ZP1 is based on a dye called fluorescein, but in the sensor this is modified to fluoresce only when it binds with zinc.
The scientists acknowledge that they had difficulty targeting specific structures within the cells, and Robert Radford, an MIT postdoc and author of the study, explains:
"We have had some success using proteins and peptides to target small molecule zinc sensors, but most of the time the sensors get captured in acidic vesicles within the cell and become inactive."
Scientists can track the location of zinc within cells and are gaining a better understanding of the role the mineral plays in cancerous cells.
To overcome these obstacles, the researchers made two changes to the sensor's design. First, they installed a zinc-reacting protecting ring, which changed its physical properties and made it easier to target.
They also attached an "address tag" to the ZP1, directing it to the mitochondria. This tag, a derivative of triphenylphosphonium, is both positively charged and hydrophobic, and the sensor successfully entered cells. This allowed the researchers to visualize pools of mobile zinc within the mitochondria.
Christopher Chang, a professor of chemistry and molecular and cell biology at the University of California-Berkeley, who was not part of the research team, says:
"This is an exciting new concept for sensing using a combination of reaction- and recognition-based approaches, which has potential applications for diagnostics involving zinc misregulation."
The role of zinc in prostate cancer cells
The scientists are already using the sensor to help them understand why zinc levels, which are normally very high in the prostate, drop dramatically in cancerous prostate cells.
"We can use these tools to study zinc trafficking within prostate cells, both healthy and diseased. By doing so we're trying to gain insight into how zinc levels within the cell change during the progression of prostate cancer."
According to the Centers for Disease Control and Prevention (CDC), prostate cancer is the most common cancer among American men and is one of the leading causes of death.
The MIT scientists are now exploring ways of using similar fluorescent sensors to create a diagnostic test, as prostate cancer is treatable if caught early enough.
It is known that zinc helps to stabilize protein structure and is the catalyst for some cellular reactions. In the prostate, zinc helps accumulate citrate, a component of semen.
Inside the mitochondria of epithelial prostate cells, zinc is known to inhibit the metabolic enzyme, aconitase. The scientists believe that by blocking aconitase, zinc shortens the citric acid cycle - the series of reactions needed to produce ATP, the cell's energy currency.
Most ATP production occurs in the mitochondria, and the MIT team theorized that when prostate cells become cancerous, they banish zinc from here, allowing the cancer cells to produce the extra energy they need to grow and divide.
"If a cell is dividing uncontrollably and it needs a lot of chemical energy, then it definitely wouldn't want zinc interfering with aconitase and preventing production of more ATP."
The scientists found that although the cancerous prostate cells absorbed the zinc, it did not collect in the mitochondira, which they claim supports the theory.
Further studies into role zinc plays in the body
The findings suggest that in healthy cells, zinc may be carried to the mitochondria by an unidentified protein. This leads the researchers to suggest that in cancer cells, the protein may be inactivated.
Future studies are being planned that will create a palette of sensors, designed to target different organelles within the cell.
The researchers are now concentrating their efforts on the role of zinc in the brain, where it is believed to work as an neurotransmitter. They will study what role zinc plays in hearing, sight and smell.
Stephen Lippard, senior author and Arthur Amos Noyes Professor of Chemistry at MIT, concludes:
"The identification of intracellular targets for mobile zinc is an important step in understanding its true function in biological signaling. The next steps will involve discovery of the specific biochemical pathways that are affected by zinc binding to receptors in the organelles, such as proteins, and elucidating the structural and attendant functional changes that occur in the process."