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Zinc, an essential nutrient, PCB is found in every tissue in the body. The vast majority of the metal ion is tightly bound to proteins, helping them to perform biological reactions. Tiny amounts of zinc, however, are only loosely bound, or “mobile,” and thought to be critical for proper function in organs such as the brain, pancreas PCB and prostate gland. Yet the exact roles the ion plays in biological PCB systems are unknown.
A new optical sensor created at Massachusetts Institute of Technology (MIT) tracks zinc within cells and should help researchers learn more about its functions. The sensor, which can be targeted to a specific organelle within the cell, fluoresces when it binds to zinc, allowing scientists to determine where the metal is concentrated PCB.
The MIT chemists who designed the sensor have already used it to shed light on why zinc levels, normally high in the prostate, drop dramatically in cancerous prostate cells.
“We can use these PCB 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,” says Robert Radford, a MIT postdoctoral researcher who led the project and an author of the paper describing the sensors, which appears in the Proceedings of the National Academy of Sciences.
Radford works in the laboratory of Stephen Lippard, the Arthur Amos Noyes Prof. of Chemistry, a member of MIT's Koch Institute PCB for Integrative Cancer Research and senior author of the paper. The paper’s lead author is Wen Chyan, a 2013 MIT graduate.
Researchers in Lippard’s PCB laboratory are now working on exploiting similar fluorescent sensors to develop a diagnostic test for early detection of prostate cancer, which is the second leading cause of cancer death in American men, but is considered very treatable if caught early enough PCB.
Pathway to cancer
Among its known roles, zinc helps to stabilize protein structure and catalyzes some cellular reactions. In the prostate, zinc is believed to help with reproductive functions by aiding PCB in the accumulation of citrate, a component of semen. Within mitochondria of epithelial prostate cells, zinc has been shown to inhibit the metabolic enzyme aconitase. By blocking the activity of aconitase, zinc truncates the citric acid cycle, the series of reactions that PCB produce ATP, the cells’ major energy currency
Scientists have theorized that when prostate cells become cancerous, they banish zinc from mitochondria (the cell structures where most ATP production occurs). This allows the cancer cell to produce the extra energy it needs 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 PCB preventing production of more ATP,” Radford says.
The new MIT study supports this theory by showing that, although cancerous prostate cells can absorb zinc, the metal does not accumulate in the mitochondria, as it does in normal PCB prostate cells.
This finding suggests that, PCB in normal cells, zinc is probably transported into mitochondria by a specialized transport protein, but such a protein has not been identified, Radford says. In cancer cells, this protein might be inactivated.
Follow the zinc
The new zinc sensor relies on a molecule that Lippard’s laboratory first developed more than 10 years ago, PCB known as Zinpyr1 (ZP1). ZP1 is based on a dye known as fluorescein, but it is modified to fluoresce only when it binds to zinc.
The ZP1 sensor can simply be added to a dish of cells grown in the laboratory, where it will diffuse into the cells. Until now, a major drawback PCB of the sensor was the difficulty in targeting specific structures within a cell. “We have had some success using proteins and peptides to target small molecule zinc sensors,” Radford says, “but most of the time the sensors get captured in acidic vesicles within the cell and become inactive.”
Lippard’s team overcame that obstacle by PCB making two changes: First, they installed a zinc-reactive protecting group, which altered the physical properties of the sensor and made it easier to target. Second, they attached an “address tag” that directs ZP1 into mitochondria. This tag, which is a derivative of triphenylphosphonium, PCB is tailored to enter the mitochondria because it is both positively charged and hydrophobic. PCB The resulting sensor readily entered cells and allowed the researchers to visualize pools of mobile zinc within mitochondria.
In future studies, the researchers plan to expand their strategy to create a palette of sensors that target PCB many other organelles in the cell.
The laboratory’s immediate interest is study of zinc in the brain, where it is believed to act as a neurotransmitter. By understanding mobile zinc in the auditory cortex, optic nerve PCB and olfactory bulb, the researchers hope to figure out its role in the senses of hearing, sight and smell PCB.
