RHOA-dependent regulation of mitochondrial remodeling and cell motility in hypoxia-exposed gastric epithelial cells

Mitochondrial appearance distinctively reflects cellular stress. Hypoxia, one of the most fundamental stressors, drives tumor progression, impacting mitochondrial structure and function. RAS homolog family member A (RHOA), a key regulator of cell motility, is frequently upregulated in response to hypoxia across cancers. However, its behavior under hypoxic conditions in gastric cancer (GC) remains largely unexplored. Additionally, to what extent the role of RHOA in cell motility is mediated through an influence on mitochondrial reshaping is elusive. Here, we show that an elevated RHOA level in GC cells triggers mitochondrial shape changes, from tubular to the stress-associated lasso and donut, correlating with increased reactive oxygen species (ROS). However, RHOA-overexpressing cells experiencing hypoxia exhibited increased migration, despite reduced mitochondrial fission and ROS levels. RHO-associated coiled-coil kinase (ROCK) inhibition impaired mitochondrial shape changes, suggesting it has a role in mitochondrial remodeling. These results indicate a unique adaptive response to hypoxia, where RHOA upregulation increases motility and modulates mitochondrial plasticity in GC cells. In summary, RHOA-mediated mitochondrial reshaping might serve as a key regulator in tumor cell adaptation and migration in low-oxygen environments.