As a cell begins any process, one of the earliest decisions it must make is whether an energy source capable of completing the task exists. Like a fuel gauge in a car, new Northwestern Medicine® research suggests the cell’s mitochondria communicate their power potential through messages sent by the reactive oxygen species (ROS) they create.
“In this model, the cell is first going to the mitochondria to make sure it is fit to do whatever is being asked of it,” said Navdeep Chandel, PhD, professor in medicine-pulmonary and cell and molecular biology, and author of three recent publications on the topic. “If the mitochondria are OK, then they should find a way to communicate that fitness and in doing so they must release some amount of information. There are multiple ways that they could conduct this signaling to the rest of the cell, but we think ROS are vital to the process.”
For decades, the mitochondria – tiny organelles within a cell – have been defined by their ability to create power. Although they are also a biosynthetic hub – providing the building blocks for the creation of lipids, proteins, DNA, and more – until recently, scientific exploration has focused on their role as the cell’s “power plant,” and not as a communicator.
Conversely, ROS have been largely defined by their ability to cause cellular damage when they accumulate at toxic levels. But in a recent Molecular Cell review article, Chandel adds to the evidence accrued over the past decade that suggests mitochondrial ROS are critical for healthy cell function.
While ROS have been linked to premature aging, neurodegenerative diseases, diabetes, and cancer, the combination of recent articles published by Chandel shifts the working model to explain their role of in a range of cellular activity and homeostasis.
Following a 2011 publication in Nature with collaborator Ralph DeBerardinis at the University of Texas Southwestern, the Chandel laboratory looked to further their in vitro findings that showed when the biosynthetic and energy generating components of mitochondria are separated, only the removal of the biosynthetic mechanisms resulted in the cell’s inability to function.
“Our hypothesis is that the primary function of mitochondria evolved to conduct biosynthesis rather than create energy,” Chandel said. “That’s not to say that the energy component is not important, but the argument is that the biosynthesis is equally crucial to maintaining homeostasis. We believe that ROS emanating from mitochondria is a mode of communicating the biosynthetic fitness of the organelle.”
That same year, Chandel and colleagues published a paper in Cell Metabolism demonstrating that stem cell differentiation into fat cells required mitochondrial ROS, suggesting that mitochondria play a vital role in the decision making process in cellular differentiation.
Using the skin as a model system, the Chandel lab collaborated with members of dermatology to show how mitochondrial ROS are important for normal skin differentiation in mice. Published as the February 5 cover story in Science Signaling, Chandel proved his hypothesis by knocking out the mitochondria in the skin cells of mice. Without the mitochondria, the cells could not release ROS, causing the skin to develop a barrier defect that prevented it from holding onto water.
“This work suggests that the mitochondria are not a consequence of differentiation but instead are causal. They are an essential ingredient and a driving force,” Chandel said. “We figured out that one of the major reasons these animals had such an issue with tissue and hair follicle growth is that the mitochondria did not release ROS.”
Similar to the way scientists knocked out the ROS output of mitochondria in skin, the Chandel laboratory’s February 14 publication in Immunity showed the effects of doing the same thing in T-cells, the cells our bodies use to fight infection.
“We found that the activation of T-cells was dependent on mitochondrial ROS. A very early signal coming from the ROS dictated whether T-cells got activated or not,” Chandel said. “Combined, our research efforts have shown that mitochondria maintain homeostasis, help fight off infection, and for cells to know they are hypoxic. We’ve illustrated the physiological role of mitochondrial ROS to show the vast benefit of their existence at the correct levels.”
From a public health point of view, Chandel considers this working model to be important when considering the rise in use of antioxidants.
“Current generations have been raised on the notion that the reason we age and develop disease is being driven by ROS,” Chandel said. “There is no clinical proof that large amounts of antioxidants offer any benefit, and in some cases they are detrimental. If we’re right about our hypothesis, a sick person may not want to take too many antioxidants – like vitamin C – as they would be affecting ROS and their ability to activate T-cells.”
Having spent the past 15 years establishing mitochondria’s role in communication, Chandel knows there is still a lot of work to be done before a definitive understanding of the process is complete.
“I realize our ideas are a bit out of the conventional thinking, but I am fortunate to work for Jacob Iasha Sznajder, MD, chief of pulmonary and critical care medicine, who encourages me to be creative and values innovative science.
“Now that we have sort of established that mitochondria communicate with the rest of the cell through the release of ROS, the real hurdle is what do they hit,” he said. “The ROS have to hit something, some protein, activating or deactivating that protein, and that reaction perpetuates the signaling. That question is a huge one going forward for the field.”
A hallmark of Chandel’s approach to science is to consistently collaborate. The T-cell study was conducted by Laura Sena, a graduate student in the lab, and done in conjunction with Paul Bryce, PhD, associate professor in allergy-immunology and microbiology-immunology, Chyung-Ru Wang, PhD, professor of microbiology-immunology, Harris Perlman, PhD, associate professor in medicine-rheumatology, Murali Prakriya, PhD, associate professor in molecular pharmacology and biological chemistry, Jonathan Licht, MD, professor in medicine-hematology/oncology and Paul Schumacker, PhD, professor in pediatrics-neonatology, cell and molecular biology and medicine-pulmonary.
The skin work published in Science Signaling was done by Chandel lab member Robert Hamanaka, PhD, in conjunction with Robert Lavker, PhD, professor in dermatology, Spiro Getsios, PhD, assistant professor in dermatology and cell and molecular biology, and Cara Gottardi, PhD, associate professor in medicine-pulmonary.
The research was supported by NIH grants AR061174 and HL071643.