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Defects in mitochondria may explain many health problems observed during space travel

Source: Cell Press
Date: 11/25/2020
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For space exploration to be successful, it’s vital to understand–and find ways to address–underlying causes of the health issues that have been observed in astronauts who have spent extended periods of time off world. 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 is reporting discovery of a common thread that drives this damage: mitochondrial dysfunction. The researchers used a systems approach to look at widespread alterations affecting biological function. The findings are reported November 25 in the journal Cell.

“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,” says senior author Afshin Beheshti (@AfshinBeheshti), a principal investigator and bioinformatician at KBR in the Space Biosciences Division of the National Aeronautics and Space Administration (NASA) at Ames Research Center in California’s Silicon Valley and a visiting researcher at the Broad Institute. “What we found over and over was that something is happening with the mitochondria regulation that throws everything out of whack.”

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 all over the world. The platform contains a range of “omics” 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 says. “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.”

He explains that 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 Twins 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 activity in different cell types had been altered. 

“I was completely surprised to see that mitochondria are so important, because they weren’t on our radar,” Beheshti says. “We were focusing on all the downstream components but hadn’t made this connection.” He adds 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.

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 notes. “The low-hanging fruit now would be to test some of these drugs with animal and cell models in space.”

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Electrical signals kick off flatworm regeneration

Source: Cell Press
Date: 03/05/2019
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Unlike most multicellular animals, planarian flatworms can regrow all their body parts after they are removed. This makes them a good model for studying the phenomenon of tissue regeneration. They are also useful for exploring fundamental questions in developmental biology about what underlies large-scale anatomical patterning.

In a study publishing March 5 in Biophysical Journal, scientists report that electrical activity is the first known step in the tissue-regeneration process, starting before the earliest known genetic machinery kicks in and setting off the downstream activities of gene transcription needed to construct new heads or tails.

“It’s incredibly important to understand how cells make decisions about what to build,” says senior author Michael Levin (@drmichaellevin), director of the Allen Discovery Center at Tufts University. “We’ve found that endogenous electrical signals enable cells to communicate and make decisions about their position and overall organ structure, so they know which genes to turn on.”

The species used in the study was Dugesia japonica. When parts of this flatworm are removed, the remaining tissues regrow the missing pieces at the correct ends–whether a head or a tail. Previous studies had shown that about six hours after amputation, the first genes associated with regrowing a missing part are turned on. But until now, it wasn’t known what happened before that or what mechanisms control which genes get turned on.

In the current experiments, led by Fallon Durant, who was a graduate student at the time, the heads and tails of the flatworms were removed. The researchers used voltage-sensitive fluorescent dyes that were able to indicate the various electrical potentials of the different regions. “You can literally see the electrical activity in the tissue,” Levin says. “Within a few hours of when this activity is seen, we can start to measure changes in gene expression.”

To show that a specific voltage pattern was responsible for turning on correct genes for each wound site, the team altered the resting potentials of cells at the different ends of the worms and observed the effects. By inducing ion flows that set each wound site to head- or tail-specific voltage patterns, they can create flatworms with two heads and no tail. They also studied the relationship between this electrical signal and the well-known Wnt protein signaling pathway, functioning downstream of the voltage-mediated decision machinery.

“Most of the people working on this problem study genetic and biochemical signals like transcription factors or growth factors,” Levin says. “We’ve decided to focus on electrical signals, which are a very important part of cell-to-cell communication.” He compares the electrical signals his group studies to those that occur in the brain. “A stimulus comes in and an electrical event triggers biochemical second-messenger events in the cells and downstream activity of the electrical network, such as decision making or forming a memory,” he notes. “This electrical system is super ancient and very highly conserved.”

Future research will focus on breaking down these signals in much more detail. For example, researchers would like to know how regenerated tissues make decisions about the size, shape, and scale of the new parts that they grow and how the bioelectric circuits store changes in body patterning, as is seen in two-headed worms that continue to make two-headed animals in subsequent rounds of regeneration.

“With perhaps the exception of infectious disease, the majority of problems in health and biomedicine hinge on understanding how cells get together to build a specific organ or other structure,” Levin concludes. “If we can figure out how to manipulate these processes, we can start to develop ways to correct birth defects and address everything from traumatic injury to degenerative diseases, aging, and cancer.”

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This research was funded by an Allen Discovery Center Award from the Paul G. Allen Frontiers Group, the G. Harold and Leila Y. Foundation, the Templeton Foundation, and the National Science Foundation.

Biophysical Journal, Durant et al.: “The role of early bioelectric signals in the regeneration of planarian anterior/posterior polarity” https://www.cell.com/biophysj/fulltext/S0006-3495(19)30065-7