Abstract
The response of human primary osteoblasts exposed to simulated microgravity has been investigated and analysis of metabolomic and proteomic profiles demonstrated a prominent dysregulation of mitochondrion homeostasis. Gravitational unloading treatment induced a decrease in mitochondrial proteins, mainly affecting efficiency of the respiratory chain. Metabolomic analysis revealed that microgravity influenced several metabolic pathways; stimulating glycolysis and the pentose phosphate pathways, while the Krebs cycle was interrupted at succinate-fumarate transformation. Interestingly, proteomic analysis revealed that Complex II of the mitochondrial respiratory chain, which catalyses the biotransformation of this step, was under-represented by 50%. Accordingly, down-regulation of quinones 9 and 10 was measured. Complex III resulted in up-regulation by 60%, while Complex IV was down-regulated by 14%, accompanied by a reduction in proton transport synthesis of ATP. Finally, microgravity treatment induced an oxidative stress response, indicated by significant decreases in oxidised glutathione and antioxidant enzymes. Decrease in malate dehydrogenase induced a reverse in the malate-aspartate shuttle, contributing to dysregulation of ATP synthesis. Beta-oxidation of fatty acids was inhibited, promoting triglyceride production along with a reduction in the glycerol shuttle. Taken together, our findings suggest that microgravity may suppress bone cell functions, impairing mitochondrial energy potential and the energy state of the cell.
Highlights
IntroductionAlterations in gravity (hypergravity and/or microgravity) represent a powerful physical cue for modelling both anatomy and function of living organisms[1,2]
Since space flight began, alterations in gravity represent a powerful physical cue for modelling both anatomy and function of living organisms[1,2]
It is generally accepted that proteomics, based on mass spectrometry, allows for the relative quantitation of a large number of proteins concurrently and in a relatively unbiased manner[22], while metabolomics information supports and corroborates the effects of the differential proteins found
Summary
Alterations in gravity (hypergravity and/or microgravity) represent a powerful physical cue for modelling both anatomy and function of living organisms[1,2]. Microgravity induces pleiotropic effects in several tissues; bone, immune and nervous system, and skeletal muscle cells rearrange their cytoskeletal organisation and protein turnover, directing cells toward apoptotic death or premature senescence, altering cellular division and differentiation[11,12]. A combination of two omics techniques, proteomics and metabolomics, was used to investigate the energy homeostasis of human cells exposed to simulated microgravity Overall, this investigation drew an exhaustive picture of how mitochondria in human primary osteoblasts are functionally dysregulated by gravitational unloading. This investigation drew an exhaustive picture of how mitochondria in human primary osteoblasts are functionally dysregulated by gravitational unloading We believe these findings will contribute to a more complete understanding of the cell physio-pathological processes which accompany astronauts’ diseases. Evaluation of the biological effects of microgravity on energy homeostasis would be of help in space medicine for developing countermeasures to assure safe and effective aerospace missions
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