Inhibition of Mitochondrial Fission Reverses Simulated Microgravity-induced Osteoblast Dysfunction by Enhancing Mechanotransduction and Epigenetic Modification

Authors:

Qiu-Sheng Shi, Ya-Xin Song, Jing-Qi Cao, Jing Na, Zhi-Jie Yang, Xin-Yuan Chen, Zi-Yi Wang, Yu-Bo Fan, Li-Sha Zheng

Keywords:

Simulated microgravity; Osteoblast function; Mitochondrial fission; Mechanotransduction; Histone methylation

Abstract:

Simulated microgravity (SMG) poses substantial challenges to astronaut health, particularly impacting osteoblast function and leading to disuse osteoporosis. This study investigates the adverse effects of SMG on osteoblasts, focusing on changes in mitochondrial dynamics and their consequent effects on cellular energy metabolism and mechanotransduction pathways. We discovered that SMG significantly reduced the expression of osteoblast differentiation markers and promoted mitochondrial fission, as indicated by an increase in punctate mitochondria, a decrease in mitochondrial length, and a reduction in cristae density. These mitochondrial alterations are linked to elevated ROS levels, a decrease in ΔΨm, and a metabolic shift from oxidative phosphorylation to glycolysis, resulting in decreased ATP production, which are all indicative of mitochondrial dysfunction. Our results showed that treatment with mitochondrial division inhibitor-1 (mdivi-1), a mitochondrial fission inhibitor, effectively inhibited these SMG-induced effects, thereby maintaining mitochondrial structure and function and promoting osteoblast differentiation. Furthermore, SMG disrupted critical mechanotransduction processes, by affecting paxillin expression, the RhoA-ROCK Myosin II pathway, and actin dynamics, which subsequently altered nuclear morphology and disrupted Yes-associated protein (YAP) signaling. Notably, treatment with mdivi-1 prevented these disruptions in mechanotransduction pathways. Moreover, our study showed that SMG-induced chromatin remodeling and histone methylation, which are epigenetic barriers to osteogenic differentiation, can be reversed by targeting mitochondrial fission, further highlighting the significance of mitochondrial dynamics in osteoblast function in a SMG environment. Therefore, targeting mitochondrial fission emerges as a promising therapeutic strategy to alleviate osteoblast dysfunction under SMG conditions, providing novel approaches to maintain bone health during prolonged space missions and safeguard the astronaut well-being.

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