Jonathan Schisler, PhD, is co-senior author of a team-science study with NASA and dozens of research universities around the country to determine the driver of cellular damage during space travel.
CHAPEL HILL, NC – November 25, 2020 – For space exploration to be successful, we need to understand and address underlying causes of health issues observed in astronauts who have spent extended periods of time away from Earth. These problems include loss of bone and muscle mass, immune dysfunction, and heart and liver problems. Using data collected from a number of different resources, a multidisciplinary team led by NASA scientists reports the discovery of a common but surprising thread that drives this damage: mitochondrial dysfunction.
The researchers, who published their work in the journal Cell, used a systems approach to look at widespread alterations affecting biological function.
“We started by asking whether there is some kind of universal mechanism happening in the body in space that could explain what we’ve observed,” said senior author Afshin Beheshti, a principal investigator and bioinformatician at KBR in the Space Biosciences Division of the National Aeronautics and Space Administration (NASA), visiting researcher at the Broad Institute, and co-president at the COVID-19 International Research Team (COV-IRT).“What we found over and over was that something is happening with the mitochondria regulation that throws everything out of whack.”
Mitochondria are cell organelles that generate most of the chemical energy cells need for the biochemical reactions we all depend on for life. This chemical energy is stored in a small molecule called adenosine triphosphate (ATP), the molecular engines that rev biological processes such as muscle contraction and nerve impulse propagation.
To implicate mitochondrial dysfunction, the investigators analyzed data obtained from NASA’s GeneLab platform, a comprehensive database that includes data from animal studies, the NASA Twin Study, and samples collected from 59 astronauts over decades of space travel. Many of the scientists who participated in this study are involved with GeneLab’s Analysis Working Groups, which draw from institutions worldwide. The platform contains a range of biological data related to changes in tissues and cells that occur due to the combined effects of space radiation and microgravity, including proteomic, metabolomic, transcriptomic, and epigenomic data.
The researchers used an unbiased approach to look for correlations that could explain the widespread changes observed. “We compared all these different tissues from mice that were flown in space on two different missions, and we saw that mitochondrial dysfunction kept popping up,” Beheshti said. “We looked at problems in the liver, and saw they were caused by pathways related to the mitochondria. Then we looked at problems in the eyes and saw the same pathways. This is when we became interested in taking a deeper look.”
Jonathan Schisler, PhD, assistant professor of pharmacology and pathology & laboratory medicine at the UNC School of Medicine, is a co-senior author of the paper.
“This particular study is a great example of what team science can accomplish,” said Schisler, who is also a member of the UNC McAllister Heart Institute. “My lab focuses on the integration of complex genomic-biologic data to elucidate the relationship between complex biological functions and disease. So our expertise was a great fit for this collaboration with NASA.”
Mitochondrial suppression, as well as overcompensation that can sometimes occur because of that suppression, can lead to many systemic organ responses. They can also explain many of the common changes seen in the immune system.
Using their discoveries from mice as a starting point, the researchers then looked at whether the same mechanisms could be involved with humans in space. Examining data from the NASA Twin study, in which identical twins Scott and Mark Kelly were followed over time, the former on the International Space Station and the latter on the ground, they saw many changes in mitochondrial activity. Some of these changes could explain alterations in the distribution of immune cells that occurred in Scott during his year in space. They also used physiological data and blood and urine samples that had been collected from dozens of other astronauts to confirm that mitochondria in different cell types had been suppressed.
“I was completely surprised to see that mitochondria are so important, because they weren’t on our radar,” Beheshti said. “We were focusing on all the downstream components but hadn’t made this connection.” He added that mitochondrial dysfunction can also help explain another common problem with extended space travel—disrupted circadian rhythms. Since the team first reported their findings within NASA, other NASA scientists have begun making connections between mitochondrial changes and common space-related cardiovascular problems as well.
Schisler added, “We can now ask more specific questions regarding the relationship between mitochondrial function and space flight. One challenging aspect of mitochondrial biology is the chicken and egg discussion. Are the changes in mitochondrial function resulting from other parts of the cell not working correctly, or do the elements of space directly impact the mitochondria? It’s exciting that our study opens the door for the design of mitochondrial-specific countermeasures that could negate the impact of microgravity and radiation on our body’s cells to generate energy.”
In conjunction with this paper, and again with a large consortium research group, Schisler co-authored a companion article in Cell Reports that describes how molecular-based countermeasures can protect tissues against the damage caused by space flight.
“Future research will build upon both of these studies, allowing us to defend our astronauts from spaceflight’s pathophysiological impact on the human body so we can reach our goals of getting to Mars,” Schisler said.
The hope is that now that mitochondrial issues have been identified as a cause of so many health risks related to space travel, countermeasures could be developed to address them. “There are already many approved drugs for various mitochondrial disorders, which would make it easier to move them toward this application,” Beheshti noted. “The low-hanging fruit now would be to test some of these drugs with animal and cell models in space.”
Read more about Schisler’s collaboration with NASA.
This work was supported by the GeneLab Project at NASA Ames Research Center, through NASA’s Space Biology Program in the Division of Space Life and Physical Sciences Research and Applications (SLPSRA); the National Aeronautics and Space Administration; the National Institutes of Health; the South Carolina Established Program to Stimulate Competitive Research; the American Heart Association; and the Human Health Countermeasures Element of the NASA Human Research Program.
Darryl Waller, NASA’s Ames Research Center, 650-604-4789
Mark Derewicz, UNC School of Medicine, 919-923-0959