Multi-Omics Analysis Reveals Mitochondrial Stress as a Central Hub for Spaceflight Biological Impact

Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep-Space Exploration

“…Oxidative stress arises when the amount of free radicals exceeds the natural antioxidant capacities of the cell (Spitz et al, 2004). Exposure to space radiation, hypoxia, and microgravity enhances the cellular production of reactive oxygen and nitrogen species (ROS, RNS), as measured in 13 astronauts in long-duration (>4 months) ISS missions (Goodwin and Christofidou-Solomidou, 2018) and 59 astronauts' 8-oxo-guanosine levels in urine (da Silveira et al, 2020). Focusing on radiation-induced oxidative damage, an linear energy transfer (LET)-dependent oxidative stress response has also been observed in human immune cells ex vivo (Pariset et al, 2020a).…”

“…Mitochondrial OXPHOS and associated fatty-acid oxidation has recently been shown to be impaired in astronauts, which is consistent with their elevated systemic lipid levels (Garrett-Bakelman et al, 2019). Additional data from mice flown to space have also shown that the liver function directly regulates carbohydrate and lipid levels (da Silveira et al, 2020). Thus, changes in systemic mitochondrial function that alter substrate oxidation should alter substrate levels and liver function.…”

“…Further evidence of mitochondrial impairment in astronauts include increased mitochondrial ROS production associated with elevated 8-hydroxydeoxyguanosine (a product of DNA oxidation) and prostaglandin levels, reduced antioxidant defense mechanisms, and altered circadian rhythms with reduced NAD+/NADH ratios impairing Sirt1 deacetylation of BMAL (Nakahata et al, 2008). In fact, a multi-omic analysis of human and mouse responses to spaceflight has revealed that one of the most important physiological alterations is mitochondrial dysregulation (da Silveira et al, 2020).…”

“…Telomere length also shortened rapidly upon return to Earth, and, in general, crewmembers had many more short telomeres after spaceflight than they did before. Chronic exposure to the space-radiation environment and intimately associated DDRs, as well as a variety of stress responses, potentially contribute to telomerase-dependent and/or independent pathways of telomere maintenance (Bezdan et al, 2020;da Silveira et al, 2020;Grigorev et al, 2020 [unpublished data];Luxton et al, 2020aLuxton et al, , 2020bTrinchant et al, 2020). Although definitive mechanisms and temporal health effects of such dramatic, spaceflightassociated shifts in telomere-length dynamics are yet to be determined, results highlight the importance of monitoring individual crewmember telomere length and genome stability as a means of evaluating general health, disease, and aging risk, information that then should be considered for development of personalized aerospace medicine and countermeasures for future astronauts.…”

Multi-omic, Single-Cell, and Biochemical Profiles of Astronauts Guide Pharmacological Strategies for Returning to Gravity

“…While these findings are striking, and the suggested countermeasures plausible, it must be cautioned that these are results of an n = 2 study, plus a small confirmatory cohort of 28 astronauts. More data for longer missions need to be collected to prepare for long-duration Martian missions (Nangle et al, 2020), including new, dynamic measures from blood and serum such as cell-free nucleic acids and exomes (Bezdan, 2020), miRNAs (Malkani, 2020), telomere dynamics (Luxton, 2020), and mitochondrial stress (Silveira, 2020). Also, while some of these biochemical and genetic signatures are recurrent, not every astronaut will exhibit the same biochemical profile shifts or respond the same way to the same medical interventions (Vernice et al, 2020).…”