Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact, 2020, Silveira et al.

[SNT Gatchaman]

Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact
Willian A. da Silveira; Hossein Fazelinia; Sara Brin Rosenthal; Evagelia C. Laiakis; Man S. Kim; Cem Meydan; Yared Kidane; Komal S. Rathi; Scott M. Smith; Benjamin Stear; Yue Ying; Yuanchao Zhang; Jonathan Foox; Susana Zanello; Brian Crucian; Dong Wang; Adrienne Nugent; Helio A. Costa; Sara R. Zwart; Sonja Schrepfer; R.A. Leo Elworth; Nicolae Sapoval; Todd Treangen; Matthew MacKay; Nandan S. Gokhale; Stacy M. Horner; Larry N. Singh; Douglas C. Wallace; Jeffrey S. Willey; Jonathan C. Schisler; Robert Meller; J. Tyson McDonald; Kathleen M. Fisch; Gary Hardiman; Deanne Taylor; Christopher E. Mason; Sylvain V. Costes; Afshin Beheshti

Spaceflight is known to impose changes on human physiology with unknown molecular etiologies. To reveal these causes, we used a multi-omics, systems biology analytical approach using biomedical profiles from fifty-nine astronauts and data from NASA’s GeneLab derived from hundreds of samples flown in space to determine transcriptomic, proteomic, metabolomic, and epigenetic responses to spaceflight.

Overall pathway analyses on the multi-omics datasets showed significant enrichment for mitochondrial processes, as well as innate immunity, chronic inflammation, cell cycle, circadian rhythm, and olfactory functions. Importantly, NASA’s Twin Study provided a platform to confirm several of our principal findings.

Evidence of altered mitochondrial function and DNA damage was also found in the urine and blood metabolic data compiled from the astronaut cohort and NASA Twin Study data, indicating mitochondrial stress as a consistent phenotype of spaceflight.

Link | PDF (Cell)

 

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I don't think we have this one referenced already. Posting due to some cross-overs with findings reported in ME and not just for the inclusion of the phrase "two murine space missions".

 

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Our data-driven approach resulted in three discoveries. First, spaceflight effects were more evident in isolated cells than whole organs, suggesting that tissue complexity plays an essential role in response to space-related stress. Second, the liver undergoes more differential gene and protein expression changes than other organs, consistent with the role the liver plays as a dynamic and critical hub in sensing changes in blood composition and maintaining homeostasis. Finally, our comprehensive pathway analyses identified how spaceflight impacts mitochondrial func- tion at the genetic, protein, and metabolite levels of cellular, tissue, and organismal biology.

Our results in muscle tissue are consistent with previous findings, suggesting reduced muscle loading due to microgravity is a strong driver of gene regulation that can influence transcriptional responses to spaceflight.

We found one overlapping collection of gene sets across all four cell types (fibroblasts, endothelial cells, primary T cells, and hair follicles). Remarkably, this overlap contained multiple mitochondrial function gene ontology (GO) terms: mitochondrial ATP synthesis, mitochondrial electron transport, oxidative phosphorylation (OXPHOS), and hydrogen ion transmembrane transportation. These data support the concept that spaceflight causes a universal change in gene expression related to energy generation.

Our analyses suggest that tissues vary in their stress response to spaceflight as it pertains to mitochondrial function. Alternatively, our observation could reflect different adaptive energy requirements of each tissue.

 

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With mouse and human astronaut subjects, including Mark and Scott Kelly who are identical twins (Mark 1 year on the ISS). This led to an excellent cohort descriptor of flight vs healthy control — which in this case is termed "ground control"

We observed mitochondrial dysfunction as a significant consequence of long-term space fight in both mouse models and humans by comparing spaceflight versus ground-based twins. Observed changes include altered mitochondria-associated metabolites and modified nuclear DNA (nDNA) and mtDNA OXPHOS gene expression, reduced antioxidant defenses and increased urinary markers of oxidative stress, and altered integrated stress response (ISR) gene expression.

These observations support the conclusion that spaceflight suppresses nDNA-coded mitochondrial OXPHOS gene expression predominantly in oxidative tissues, and the induction of the mtDNA genes partially compensates for the diminished mitochondrial oxidative metabolism.

The reason for the opposite changes in transcription of the nDNA- and mtDNA-coded mitochondrial OXPHOS genes in spaceflight is unclear, but our results suggest that oxidative damage contributes to decreased nDNA OXPHOS transcripts.

If these opposite trends in the differential transcription of the nDNA- and mtDNA-coded mitochondrial OXPHOS genes extend to the protein level, this would lead to imbalances in the assembly of OXPHOS complexes and promote the mitochondrial unfolded protein response (UPRMT).

 

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We investigated astronaut data to support the evidence of the biological processes observed in spaceflight mice. First, we analyzed the global mitochondrial levels from different cell populations (T lymphocytes CD4+ and CD8+, B lymphocyte CD19+, and lymphocyte-depleted [LD] cells) in the blood from the NASA Twin Study.

Although the mitochondrial levels between the twin in space compared to the GC differed pre-flight, we observed a signifi- cant shift in mitochondrial activity from FLT to post-flight compared to pre-flight. CD19 cells had the greatest increase in mitochondrial activity post-flight for the twin in space, while mitochondrial activity in the CD4 population was significantly reduced FLT and post-flight.

Next, we measured the expression of five mtDNA genes related to OXPHOS [...] All five mtDNA genes showed a similar pattern in response to spaceflight, starting with a 2- to 3-fold increase in expression at the beginning of the twin’s time on the ISS, and the peak was at 7- to 9-fold increase toward the end of the twin’s time on the ISS. In contrast, there were no robust changes in any of the genes from matched samples for the twin on Earth

Remarkably, the mtDNA gene expression changes that occurred during spaceflight returned to baseline levels post-flight within a few weeks.

Results for flux comparisons between flight and control mice show several notable metabolic pathway groups with opposite trends in muscle versus liver in both mitochondrial activity and oxidative stress

Cell culture models found an overall upregulation in immune-related pathways during spaceflight. In the internal organs, there was also a high presence of activated innate immune system pathways. Immune response through interferon-gamma (IFN-g) and interferon-alpha (IFN-a) gene sets were downregulated in the kidney and liver, with the epigenetic analysis showing differential methylation of these same gene sets

 

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Also, the lipid profile in astronauts changed with spaceflight. We found higher levels of total cholesterol and low-density lipoprotein (LDL) cholesterol accompanied by decreased levels of high-density lipoprotein (HDL) cholesterol. Again, these levels re- verted to normal after returning to Earth.

Also, the lipid profile in astronauts changed with spaceflight. We found higher levels of total cholesterol and low-density lipoprotein (LDL) cholesterol accompanied by decreased levels of high-density lipoprotein (HDL) cholesterol. Again, these levels re- verted to normal after returning to Earth.

Finally, our multi-omics analysis of spaceflight biology identified a grouping of pathways related to the circadian rhythm, olfactory activity, synapse-receptor signaling, and muscle extracellular matrix (ECM).

Circadian rhythm pathways were upregulated at the transcriptional level in all internal organs but the liver, suggesting that spaceflight impacts diurnal patterns of gene expression.

 

[SNT Gatchaman]

I might suggest that having a deep understanding of the pathophysiology of ME/CFS might be beneficial for this century's space missions (and beyond).

Oxidative stress is critical to mitochondria-mediated disease processes. The longitudinal decrease in antioxidant capacity observed in astronauts during spaceflight agrees with the development of mitochondrial and metabolic impairment dependent on space exposure. Energy homeostasis is of great importance when considering extended duration space missions, such as the possible mission to Mars, that will last at least 560 days.

 

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See also —

The effects of real and simulated microgravity on cellular mitochondrial function (2021, Nature npj Microgravity)

Cell‐Free Mitochondrial DNA as a Potential Biomarker for Astronauts' Health (2021, Journal of the American Heart Association)