Overexpression of catalase in mitochondria mitigates changes in hippocampal cytokine expression following simulated microgravity and isolation

Linda Rubinstein,Samantha M Torres,Antiño R Allen,Ann-Sofie Schreurs,Candice G T Tahimic,Frederico Kiffer,Sonette Steczina,Marianne B Sowa,Ruth K Globus,Moniece G Lowe,April E Ronca

doi:10.1038/s41526-021-00152-w

Abstract

Isolation on Earth can alter physiology and signaling of organs systems, including the central nervous system. Although not in complete solitude, astronauts operate in an isolated environment during spaceflight. In this study, we determined the effects of isolation and simulated microgravity solely or combined, on the inflammatory cytokine milieu of the hippocampus. Adult female wild-type mice underwent simulated microgravity by hindlimb unloading for 30 days in single or social (paired) housing. In hippocampus, simulated microgravity and isolation each regulate a discrete repertoire of cytokines associated with inflammation. Their combined effects are not additive. A model for mitochondrial reactive oxygen species (ROS) quenching via targeted overexpression of the human catalase gene to the mitochondria (MCAT mice), are protected from isolation- and/or simulated microgravity-induced changes in cytokine expression. These findings suggest a key role for mitochondrial ROS signaling in neuroinflammatory responses to spaceflight and prolonged bedrest, isolation, and confinement on Earth.

Highlights

Isolation is an important feature of the spaceflight environment
DISCUSSION not in complete solitude, human crew in deep space missions will experience prolonged exposure to environments isolated from Earth and larger social groups
We assessed the consequence of isolation alone or in combination with simulated microgravity on the central nervous system (CNS) cytokine milieu, a key component of the neuroimmune response

Summary

INTRODUCTION

Isolation is an important feature of the spaceflight environment. Interplanetary missions (e.g., trip to Mars) will involve mission crew operating in isolated environments for prolonged periods of time. There have been few studies exploring oxidative damage as a mechanism by which space environmental factors, singly or in combination, mediate aspects of CNS immune responses To address these gaps in knowledge, HU was conducted on paired (social) and single housed wild-type and MCAT mice, a genetic model for mitochondrial ROS quenching. In this study, we tested the hypothesis that isolation and simulated microgravity lead to altered hippocampal cytokine expression via mitochondrial ROS-related mechanisms. Hippocampal alterations, e.g., oxidative damage, spatial changes, and genetic alterations have been reported in both actual and modeled microgravity[32,43,44,45,46] and linked to behavioral deficits[47] These higher CNS functions are critical for astronaut performance during extended periods of spaceflight. These findings highlight the importance of mitochondrial ROS mechanisms in CNS responses to these stressors, thereby providing a rationale for testing possible use of antioxidants to mitigate CNS risks associated with long-term space exploration as well as bedrest and isolation on Earth

RESULTS

DISCUSSION

MATERIALS AND METHODS