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Newswise – CHAPEL HILL, NC – November 25, 2020 – For space exploration to be successful, we need to understand and address the underlying causes of the health problems seen in astronauts who have spent long periods of time away from Earth. These problems include bone and muscle loss, immune dysfunction, and heart and liver problems. Using data gathered from a variety of different resources, a multidisciplinary team led by NASA scientists reports the discovery of a common but surprising thread driving this damage: mitochondrial dysfunction.
The researchers, who published their work in the journal Cell, used a systemic approach to examine the diffuse alterations affecting biological function.
“We started by wondering if there is some sort of universal mechanism happening in the body in space that could explain what we have 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-chair of the COVID-19 International Research Team (COV-IRT). “What we have discovered over and over is that something is happening with the regulation of mitochondria that knocks everything out of the head.”
Mitochondria are cellular organelles that generate most of the chemical energy needed by cells 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 motors that stimulate biological processes such as muscle contraction and nerve impulse propagation.
To implicate mitochondrial dysfunction, the researchers 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 around the world. The platform contains a range of biological data relating to changes in tissues and cells that occur due to the combined effects of spatial radiation and microgravity, including proteomic, metabolomic, transcriptomic and epigenomic data.
The researchers used an unbiased approach to look for correlations that could explain the diffuse changes observed. “We compared all of these different tissues from mice that had flown into space on two different missions, and we saw that mitochondrial dysfunction kept popping up,” Beheshti said. “We looked at the liver problems and saw that they were caused by pathways linked to the mitochondria. Then we looked the problems in the eye and saw the same paths. This is the moment we got interested in taking a deeper look. “
Jonathan Schisler, PhD, assistant professor of pharmacology and pathology and laboratory medicine at the UNC School of Medicine, is a senior co-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 integrating complex genomic-biological data to elucidate the relationship between complex biological functions and disease. So our experience was perfect for this collaboration with NASA. “
Mitochondrial suppression, as well as the overcompensation that can sometimes occur due to such suppression, can lead to many systemic organic responses. They can also explain many of the common changes seen in the immune system.
Using their findings on mice as a starting point, the researchers then examined whether the same mechanisms could be involved with humans in space. Looking at data from NASA’s twin study, in which identical twins Scott and Mark Kelly were tracked 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 the 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 collected from dozens of other astronauts to confirm that the 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 we hadn’t established this link.” He added that mitochondrial dysfunction may also help explain another common problem with prolonged space travel: disrupted circadian rhythms. Since the team first reported their findings to NASA, other NASA scientists have begun to make connections between mitochondrial changes and common space-related cardiovascular problems.
Schisler added: “We can now ask more specific questions about the relationship between mitochondrial function and space flight. A challenging aspect of mitochondrial biology is the chicken and egg discussion. Changes in mitochondrial function from other parts of the cell don’t work. correctly?, or do the elements of space have a direct impact on the mitochondria? It is exciting that our study opens the door to the design of specific mitochondrial countermeasures that could nullify the impact of microgravity and radiation on the cells of our body to generate energy ” .
In collaboration with this article, and again with a large consortium research group, Schisler is co-author of a complementary article in Cell reports describing how molecular-based countermeasures can protect tissues from damage caused by space flight.
“Future research will build on both of these studies, allowing us to defend our astronauts from the pathophysiological impact of spaceflight on the human body so that we can achieve our goals of getting to Mars,” Schisler said.
The hope is that now that mitochondrial problems have been identified as the cause of so many health risks related to space travel, countermeasures can be developed to address them. “There are already many drugs approved for various mitochondrial disorders, which would make it easier to move them to this application,” Beheshti noted. “The lowest fruit now would be to test some of these drugs with animal and cell models in space.”
Learn more about Schisler’s collaboration with NASA.
This work was supported by the GeneLab project at NASA’s Ames Research Center, through NASA’s Space Biology Program in the Division of Research and Applications of Space Life and Physical Sciences (SLPSRA); the National Aeronautics and Space Administration; the National Institutes of Health; the program established in South Carolina to stimulate competitive research; the American Heart Association; and the human health countermeasures element of NASA’s human research program.
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