Mitochondrial Changes Key to Health Problems in Space

From NASA Ames

Nov. 25, 2020

Living in space isn’t easy. There are notable impacts on the biology of living things in the harsh environment of space. A team of scientists has now identified a possible underlying driver of these impacts: the powerhouse of the cell, called mitochondria, experiences changes in activity during spaceflight.

Recently published in the journal Cell, these results used data collected over decades of experimental research on the International Space Station, including samples from 59 astronautsStudies such as these are critical to understanding the effects of low gravity, radiation, confined spaces, and more as NASA sends astronauts deep into space for extended missions to the Moon, Mars, and beyond.

Scientist, to the right, sitting at a lab desk pipetting into a set of samples. There's a large machine to the left.
Valery Boyko, lead of NASA GeneLab’s Sample Processing Lab, is setting up automated liquid handling instrument to quantify the amount of sequencing material in a sample.Credits: NASA/Dominic Hart

“We’ve found a universal mechanism that explains the kinds of changes we see to the body in space, and in a place we didn’t expect,” said Afshin Beheshti the lead author on the paper and a researcher with KBR, which provides contract support to NASA’s Ames Research Center in California’s Silicon Valley. “Everything gets thrown out of whack and it all starts with the mitochondria.”

The research also made use of a comprehensive database of animal studies collected on the GeneLab platform at Ames, as well as the NASA twin study comparing identical twins Mark and Scott Kelly over the course of a year. The GeneLab platform is the first of its kind to capture large amounts of space biology “omics” data that can be used to characterize and quantify biological molecules – such as DNA, RNA, and proteins – and their systematic effects on the structures and functions of organisms. GeneLab’s Analysis Working Group drew in scientists from all over the world to collaborate on the study and get the most out of the data housed on the open-source platform.

Mitochondria are tiny structures within cells that produce energy for the basic units of biology that make up our bodies. When that energy production breaks down, many of the body’s key organs and its immune system can be put in jeopardy. This new research indicates this breakdown in activity of mitochondria might contribute to health or performance challenges faced by humans in space.

The first clue about the connection between mitochondria and spaceflight came from research using rodents.

“When we started comparing the tissues from mice flown on separate space missions, we noticed that mitochondrial dysfunction kept popping up,” said Beheshti. “Whether we were looking at problems in the eyes or in the liver, the same pathways related to mitochondria were the source of the problem.”

NASA’s data on humans backed this hypothesis up. The changes identified in astronaut Scott Kelly’s immune system during his year in space starting in 2015 may be explained by the changes observed in the activity of his mitochondria as well. Blood and urine samples from dozens of other astronauts showed further evidence that, in various types of cells, being in space led to altered mitochondrial activity.

“This is a big step toward figuring out how our bodies can live healthily off-world,” said Beheshti. “And the good news is, this is a problem we can already start to tackle. We can look at countermeasures and drugs we already use to deal with mitochondrial disorders on Earth to see how they might work in space, to start.”

From issues as wide-ranging as disrupted circadian rhythms to cardiovascular alterations, scientists can now turn to this small but essential structure in cells as a place to continue research and look for solutions. Mitochondria are indeed the powerhouse of the cell, and may also power the future of space biology research – pointing the way toward discoveries that will help astronauts live safely in orbit and beyond.

For news media:

Members of the news media interested in covering this topic should reach out to the NASA Ames newsroom.

Author: Frank Tavares, NASA’s Ames Research Center

Top image: Astronaut Scott Kelly is working with the Microgravity Sciences Glovebox during a Rodent Research session with Bone Densitometer. Credit: NASA
Last Updated: Nov. 30, 2020
Editor: Frank Tavares

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Joel O’Bryan
December 3, 2020 12:09 am

Mitochondria has its own DNA, a circle of DNA not maintained like chromosomal DNA that has ends and telomeres.
mtDNA doesn’t not have as efficient a mtDNA repair pathways as chromosomal DNA in the nucleus. There likely an evolutionary reason for that. Its sort of like our throw away consumer world today, where it is easier to discard a broken toaster than repair it a natural evolution. But if your house breaks, though you repair because the cost to replace with new is too high in most cases. Similarly it is easier for a cell just to discard a damaged mitochondria and its mtDNA, since most cells have hundreds of mitochondria, than to repair. Evolution at work. But if enough mitochondria are being simultaneously damaged, the replacement process can’t keep up.
So in spoace, mitochondria are likely being damaged at a much higher rate, more precisely probably the mtDNA by ionizing radiation, especially G-rich sequences which are abundant in mtDNA.

bonbon
Reply to  Joel O’Bryan
December 3, 2020 3:20 am

From The Cell Article, with very good images,

https://www.cell.com/cell/fulltext/S0092-8674(20)31461-6?from=article_link

“These data support the concept that spaceflight causes a universal change in gene expression related to energy generation.”

Do they mean a slowdown in energy generation?

Charles Higley
Reply to  bonbon
December 3, 2020 7:29 am

We know that low oxygen conditions, which is a main ingredient in normal aerobic metabolism in mitochondria, leads to depression of the immune system, which then can lead to many other effects as a result of ionizing radiation of nuclear DNA. It would be interesting to see how mitochondria due on Mars surfaces, where radiation might be less. Maybe we end up scurrying from planet to planet and avoiding long periods in space.

Robert of Ottawa
Reply to  Charles Higley
December 3, 2020 10:29 pm

No, we end up building spacecaft that are truly enormous and powerful, that allow us to provide a much safer environment. I am talking of, in hte “near” future, craft a mile or more in length, fission powered, These would make our solar system accessible.

Future human spacecraft to other stars woul be 10 times this size, fusion powered.

kwinterkorn
Reply to  Robert of Ottawa
December 4, 2020 5:00 pm

The spacecraft do not need to be huge, but they need to have the human-occupied compartments shielded from both solar and cosmic radiation. I have read that approximately 1.5 meter thickness of water is about right for passive shielding. The water also can be used for drinking and split into hydrogen and oxygen for breathing and rocket fuel.

The main problem is the weight. Magnetic shielding to deflect charged particles has problems, too.
,

John Tillman
Reply to  Joel O’Bryan
December 3, 2020 4:08 am

Most of the original mitochondrion’s DNA has migrated into the nuclei of eukaryotic cells. The bits which remain in the two types of mitochondrial circular chromosomes, heavy and light, encode 13 proteins and 24 RNA sequences, all involved in oxidative phosphorylation. Mitochondria require some 1500 proteins, so the vast majority of their genes now lie in the nucleus. Only those involved in the ATP energy process have been retained.

The heavy chromosome is rich in guanine.

Learning how to repair mitochondria will benefit not just space travelers.

gringojay
Reply to  John Tillman
December 3, 2020 8:39 am

Each mitochondria has 5-10 copies of it’s genes there; unlike our nucleus with 2 copies of each gene there. (One estimate is that originally mitochondria had about 4 thousand genes.) .In comparison to nucleus located genes mitochondrial genes historically evolve 10 – 50 times faster.

Each of our cells that divide also result in the daughter cell getting a different number of mitochondria than the cell derived from. Thus through time a daughter cell statistically will get a different ratio of mitochondrial mutations than the cell derived from; the effect may be for the better or worse depending on the mitochondrial mutation.

John Tillman
Reply to  gringojay
December 3, 2020 10:30 am

Mitochondria appear most closely related to alphaproteobacterial Genus Rickettsia. As obligate intercellular parasites, Rickettsia have reduced genomes, but less radically than mitochondria. A sequenced species has 834 genes.

But it makes sense that the alphaproteobacterium ancestral to mitochondria and Rickettsia had a few thousand protein-coding sequences.

cedarhill
Reply to  Joel O’Bryan
December 3, 2020 7:26 am

One should read Seyfried’s Cancer as a Metabolic Disease which reviews the internal cellular biology of dysfunctional mitochondria and it’s impact (2014 – available free on PubMed). Damaged mitochondria is very real and very dangerous to humans. Dr. Seyfried runs the cell microbiology lab at Boston U.

Obtw, the mitochondria, per Darwin, etc., were a bacterium the human cells engulfed eons ago. A symbiosis. Which is why they have separate DNA and why ancestry can be traced on the mothers side since each persons mitochondria is from the only mother via the ovum (i.e., sperm only has the human DNA).

And, there’s lots of cellular biology discoveries where the mitochondria “communicate” to the cell’ nucleus along with their epigenetic impact on gene expression.

gringojay
Reply to  cedarhill
December 3, 2020 8:56 am

There are about 10,000 mitochondria inside the female human egg. To reduce the mitochondrial mutation rate those produced are decoupled relatively early while the ovary continues to develop embryonically. The cellular germline, which can divide forever, is turned off for those egg cell mitochondria.

Carl Friis-Hansen
December 3, 2020 2:29 am

Interesting article about mitochondria which leads me to announce this interview with Dr Kary Mullis, who got the Nobel Price for the invention of the PCR test.
In this interview it is about the scientific community, the process and the not knowing anything loud speaking “scientists”. Because the interview is old, it is about AIDS and HIV, but it relates to any virus and infection and they way it is pursued. – And Fauci’s business model.
PCR tests inventor, Nobel Laureate Dr Kary Mullis Drops Truth Bombs About HIV/AIDS

icisil
Reply to  Carl Friis-Hansen
December 3, 2020 7:02 am

Virologists hoodwinked Reagan and Congress into pouring money into AIDS research. In the beginning it was very obviously an immuno-compromised condition caused by heavy recreational drug use. For example, the only AIDS patients who got the rare Kaposi’s Sarcoma were heavy abusers of “poppers” (amyl nitrates); and more than a few gays who got KS tested negative for HIV, but they were still diagnosed with AIDS. Researchers like Duesberg said as much, but virologists ignored and maligned them, and eventually prevailed. Later blood transfusion recipients were added to the list. Then pharmaceutical drugs started claiming victims, but virologists insisted it was due to AIDS. I remember the watershed event that made AIDS mainstream. A young woman tested positive, and they claimed she caught AIDS from her dentist. She was one of the first straight people to receive AZT. Give someone chemotherapy for a couple of weeks and they might live, but give it to them for weeks and months and years, like they did with AIDS patients, and they will almost certainly die. I’m convinced that’s what happened to her.

And they’re doing the same thing now with preemptive/early mechanical ventilation, which before covid was only used as a last resort due to its potential for patient harm. After just 4-5 hours of mechanical ventilation, inflammatory markers become significantly elevated in surgery patients, especially obese patients. Ventilate patients for days and weeks and months, though, as they do with covid patients, and it can cause excessive inflammation and out-of-control immune response that leads to multiple organ failure, the very things blamed on the virus.

icisil
Reply to  icisil
December 3, 2020 7:42 am

Parking this here because it’s relevant to what I just said and it just happens to be something I’m studying at the moment. See the connection?

Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients
https://rupress.org/jem/article/218/3/e20201707/211560/Inflammasomes-are-activated-in-response-to-SARS?

Inflammasome Impacts Lung Injury in Patients Who Receive Mechanical Ventilation
https://www.elitecme.com/resource-center/respiratory-care-sleep-medicine/inflammasome-impacts-lung-injury-in-patients-who-receive-mechanical-ventilation

icisil
Reply to  icisil
December 3, 2020 7:59 am

Here’s another biomarker in case anyone is interested. There are others…

VEGF-D: a novel biomarker for detection of COVID-19 progression
https://ccforum.biomedcentral.com/articles/10.1186/s13054-020-03079-y

Ventilator-induced lung injury (VILI) increases expression of endothelial inflammatory mediators in the kidney
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407070/

We also observed increased VEGF levels in the kidney in VILI compared with systemic inflammation in CLP. It is possible that cytokines and damage-associated molecular patterns (DAMPs) released during VILI trigger de novo VEGF production in the kidney. Another possibility is that the VEGF in the kidney is of lung origin, as lung tissue has among the highest levels of VEGF in the body (22, 24). Damage to the alveolar capillary membrane during VILI could lead to a massive release of VEGF into systemic circulation and reach the kidney through this mechanism. However, corresponding levels of other vascular effector proteins (discussed below) increased in the VILI groups suggest de novo effects in the kidney. Further research into these possible mechanisms is required to elucidate pathophysiology of biotrauma. Nonetheless, our findings suggest that renal VEGF may be a useful biomarker of distant organ injury in the kidney due to VILI.

Ian Coleman
Reply to  icisil
December 3, 2020 7:34 pm

Oh, icicsil. AIDS was spread by a bloodborne virus. There is just no way to get around the evidence. Why did blood transfusions to uninfected people result in HIV-positivity and then AIDS? Poppers caused AIDS? That’s a very thin string to hang a heavy weight. Popper use was not confined to gay men but, at least in the early days of the epidemic, gay men were overwhelmingly the carriers of and sufferers from HIV. The treatments for AIDS today are antivirals.

michael hart
December 3, 2020 3:12 am

Mitochondrial activity is the key to health, period. Full stop. Not just in space.

Tom Abbott
December 3, 2020 10:12 am

A shield made of water ice, one meter thick, will stop space radiation from injuring human beings.

John Tillman
Reply to  Tom Abbott
December 3, 2020 10:33 am

Unfortunately water, even in solid phase, is heavy.

John Tillman
Reply to  John Tillman
December 3, 2020 10:34 am

I guess I should say massive once out of Earth’s gravitational frame.

Tom Abbott
Reply to  John Tillman
December 4, 2020 7:31 am

Yes, you have to be technical around here. 🙂

Yes, water ice is heavy, but we can work around that problem. We will have to work around that problem if humans want to live safely in space, because we must have radiation shielding for any kind of long-term living in space.

Large human habitats in space will have thick walls to protect the inhabitants. Hollowing out a small asteriod might be the easiest way to build a protective habitat quickly.

Water ice would be good to use on an orbital transfer vehicle that travels regularly between Earth orbit and Mars orbit. Buzz Aldrin has worked out a way to put vehicles (cycling space stations, he calls them) in this kind of orbit. Once placed in this orbit very little extra propellant is needed to keep it in this orbit.

The Cycling Space Station orbits back and forth between Earth and Mars and when you want to go to Mars, you get yourself an orbital transfer vehicle and you fly out to meet the Cycling Space Station, and you transfer yourself and cargo to the Cycling Space Station and then you are off to the Red Planet.

When you get to the Red Planet, an orbital transfer vehicle will meet the Cycling Space Station and transfer you and your cargo to the base in orbit around Mar’s moon Phobos. And the Cycling Space Station heads back toward Earth orbit.

Putting more than one Cycling Space Station in service at the same time would allow you to space out the arrivals and departutes to where you would have the opportunity to travel to Mars or back to Earth every couple of months.

The Cycling Space Stations could be covered with a water ice shield (or portions thereof) to protect the passengers, and yes, it would cost extra propellant to get this vehicle moving but once it is in its orbit, no more propellant is required to keep it in this orbit, other than for ordinary stationkeeping.

And, if we could put two of these vehciles together and separate them by a one-mile-long cable, and then rotate these two vehicles around the center of the system, at one revolution per minute, this would creat artificial gravity (centrifugal force) on the habitat modules equivalent to the gravity on the surface of the Earth.

We could combine radiation protection and Earth-equivalent “gravity” with this Cycling Space Station configuration.

And we don’t really need a second Cycling Space Station for this configuration, all we need is enough mass on the other end of the cable that equals the mass of the Cycling Space Station. We would need a method to stationkeep that mass. Attached thrusters would do the trick.

I’ll be interested to compare Musk’s launch costs to get to Mars with using something like the Cycling Space Station to do the same job. As far as safety goes, Musk’s plan cannot compare to setting up a Cycling Space Station system, since it does not eliminate radiation risks and low-gravity risks on the trips back and forth to Mars..

Hoser
Reply to  Tom Abbott
December 3, 2020 5:45 pm

If the worry is neutrons, then you can use LCH4 the fuel you may be carrying around with you anyway.

Jon
December 3, 2020 12:15 pm

I blame global warming.

gringojay
December 3, 2020 12:24 pm

Cited report says liver nuclear coded cytochrome c & co-enzyme Q are “strongly down regulated”. The mitochondria shuttling of electrons stripped from hydrogen that was bound to carbon is meant to occur in the mitochondrial complex one.

Complex I of mitochondria has 45 separate proteins, each made up of hundreds of amino acids. And in this complex there are 9 reduction and oxidation “REDOX” centers (reduced = accepts electron & oxidized = passes along electron) involving clusters of iron and sulphur (Fe-S clusters) forming around quantum tunnels of mostly 7 – 14 angstroms space.

Meanwhile, once the electron gets through all those Fe-S clusters it goes to ubiquinone for passing to the next mitochondrial cluster; ubiquinone is “co-enzyme Q”, which apparently is limited in the liver during space travel.

As for the limited cytochrome c in space travel: this protein (enzyme) shuttles electrons from the third to the fourth complex (complex III to IV) of a mitochodria.

Continues …

gringojay
Reply to  gringojay
December 3, 2020 1:31 pm

(cont.) Cited research decries the negative implications of reactive oxygen (ROS) in space travel. The most ROS is generated in the 1st mitochondrial complex.

The Complex I Fe-S clusters is where Fe+++ gets an electron (is reduced) to form Fe++; the Fe++ can react with oxygen to make a reactive oxygen for having a single un-paired electron, called super-oxide. It is the variable angstrom distances among the 9 REDOX center of Complex I which permit electrons stray movement to a quantum tunnel & interaction with a free oxygen to act on.

The cited liver related deficit of co-enzyme Q , which is tasked with getting the electrons that actually navigate beyond Fe-S clusters to their next phase, means there is limited onward processing. In other words, there is sluggish flux of electrons & there are more electrons in the 1st complex of a mitochondria; which in turn creates the conditions for increased reactivity with oxygen & thus elevates the ROS super-oxide.

Which segues us to the cited reduction of cytochrome c in space traveling livers. At the 3rd complex of a mitochondria cytochrome c shuttles electrons from there to the 4th complex of that mitochondria (the shuttling of electrons causes protons to be pumped across the mitochondrial membrane at the different complexes, except for no protons get pumped at the 2nd mitochondrial complex).

Cytochrome c is very lightly held at a mitochondrial complex by a molecule (cardiolipin) on the mitochondrial membrane. The issue is too long exposure to the ROS super-oxide becomes reactive with the molecule cardiolipin co-joined to mitochondrial cytochrome c provoking a lost relationship as cytochrome c disassociates from the mitochondrial membrane.

At the mitochondrial Complex III this displacement of cytochrome c, which in cited report is already down-regulated in space travel, means there is a reduction in the flux of electrons progressively moving along to Complex IV & with ensuing ROS leaking (NO binding to cytochrome c provokes ROS leak) from the mitochondria the mitochondrial membrane charge (electro-potential) falls leading to reduced ATP production.

It should be understood that a single mitochondria can have tens of thousands of copies of each mitochondrial complex. And our 40 trillion different human cells can have a hundred to thousands of mitochondria.

gringojay
Reply to  gringojay
December 3, 2020 1:49 pm

Study concludes “… reduced mitochondrial function … activate … mtDNA replication …” This is because elevated super-oxide, acting as a signaling molecule, instigates a transcription factor that is responsive to REDOX conditions ( where the oxidation of cysteine elicits bio-genesis of new mitochondria once mitochondria’s topo-ismer-ase I enzyme confers access of it to a mitochondria’s DNA).

Study summarizes that the excessive replication of mitochondrial DNA in the context of elevated ROS then results in mitochondrial DNA being oxidized. This oxidized form of mitochondrial DNA is then an actor in some of the changes reported in space travel physiology.

gringojay
Reply to  gringojay
December 3, 2020 1:54 pm

edit: topo-isomer-ase correction (last sentence of 1st paragraph above)

Weylan R McAnally
Reply to  gringojay
December 3, 2020 3:24 pm

So supplementation with Iron, sulfur, CoQ10 and R-alpha lipoic acid should diminish the impact of space on mitochondria? That is my take on your explanation. Of course, I could be wrong

john cooknell
December 3, 2020 1:11 pm

Read this stuff ended up thinking “maybe”.

Kpar
December 3, 2020 5:26 pm

Well, now we know what happened to Scott Kelly. But that does not explain the people who voted for him.

Then again, there weren’t really that many who did.

J Mac
December 4, 2020 11:40 am

Excellent. A true ‘root cause’ determination guides effective corrective actions! May this further assist our toddling efforts to leave the home crib and explore our solar system neighborhood.

pochas94
December 6, 2020 5:53 am

97.5% of what you read nowadays is BS. That’s why I’m such a slow learner. I read “Scott’s mental abilities had declined from preflight levels. He was slower and less accurate on short-term memory and logic tests.” Why, I’m having the same problem and I’ve never been higher than 40,000 feet.

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