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Article
Comprehensive Multi-omics Analysis Reveals
Mitochondrial Stress as a Central Biological Hub
for Spaceflight Impact
Willian A. da Silveira,1,23 Hossein Fazelinia,2,23 Sara Brin Rosenthal,3,23 Evagelia C. Laiakis,4,23 Man S. Kim,2,23
Cem Meydan,5,23 Yared Kidane,6,23 Komal S. Rathi,2,23 Scott M. Smith,7 Benjamin Stear,2 Yue Ying,2 Yuanchao Zhang,2
Jonathan Foox,5 Susana Zanello,8 Brian Crucian,7 Dong Wang,9 Adrienne Nugent,10 Helio A. Costa,11 Sara R. Zwart,12
Sonja Schrepfer,9 R.A. Leo Elworth,13 Nicolae Sapoval,13 Todd Treangen,13 Matthew MacKay,5 Nandan S. Gokhale,14
Stacy M. Horner,14 Larry N. Singh,15 Douglas C. Wallace,15,16 Jeffrey S. Willey,17,24 Jonathan C. Schisler,18,24
Robert Meller,19,24 J. Tyson McDonald,4,24 Kathleen M. Fisch,3,24 Gary Hardiman,1,20,24 Deanne Taylor,2,15,16,24
Christopher E. Mason,5,24 Sylvain V. Costes,21,24 and Afshin Beheshti22,24,25,*
1Queens University Belfast, Belfast BT9 5DL, UK
2The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
3University of California San Diego, La Jolla, CA 92093, USA
4Georgetown University Medical Center, Washington D.C. 20057, USA
5Weill Cornell Medical College, New York, NY 10065, USA
6Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA
7NASA Johnson Space Center, Houston, TX 77058, USA
8imec USA, Kissimmee, FL 34744, USA
9University of California San Francisco, San Francisco, CA 94115, USA
10Hampton University, Hampton, VA 23669, USA
11Stanford University, Stanford, CA 94305, USA
12University of Texas Medical Branch, Galveston, TX 77555, USA
13Rice University, Houston, TX 77005, USA
14Duke University Medical Center, Durham, NC 27710, USA
15Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
16Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
17Wake Forest School of Medicine, Winston-Salem, NC 27101, USA
18The University of North Carolina at Chapel Hill, NC 27599, USA
19Morehouse School of Medicine, Atlanta, GA 30310, USA
20Medical University of South Carolina, Charleston, SC 29425, USA
21NASA Ames Research Center, Moffett Field, CA 94035, USA
22KBR, NASA Ames Research Center, Moffett Field, CA 94035, USA
23These authors contributed equally
24Senior author
25Lead Contact

*Correspondence: afshin.beheshti@nasa.gov
https://doi.org/10.1016/j.cell.2020.11.002

SUMMARY

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 deter-
mine transcriptomic, proteomic, metabolomic, and epigenetic responses to spaceflight. Overall pathway ana-
lyses 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.

INTRODUCTION Moon and planned manned missions to Mars (Dawson, 2016).

Exposure to space radiation and microgravity are primary haz-
Humanity is on the brink of a new era in space exploration, with ards to astronauts’ health in long-duration space missions (Gar-
NASA and international partners committed to returning to the rett-Bakelman et al., 2019). In addition to the known increased

Cell 183, 1185–1201, November 25, 2020 ª 2020 Elsevier Inc. 1185