Pal Aranya, Bawali Prabin, Brahma Abhisek, Rana Smruti Ranjan, Mohapatra Rakesh, Chakraborty Debashish, Poirah Indrajit, Samal Supriya, Banerjee Smaran, Smoot Duane T, Ashktorab Hassan, Bhattacharyya Asima
School of Biological Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, An OCC of Homi Bhabha National Institute, P.O. Bhimpur-Padanpur, Via Jatni, Dist. Khurda 752050, Odisha, India.
Department of Infectious Disease Biology, Institute of Life Sciences, NALCO Square, Chandrasekharpur, Bhubaneswar, Odisha, 751023, India.
J Cell Sci. 2025 Jul 15;138(14). doi: 10.1242/jcs.263690. Epub 2025 Jul 30.
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.
线粒体的外观独特地反映了细胞应激。缺氧是最基本的应激源之一，它驱动肿瘤进展，影响线粒体的结构和功能。RAS同源家族成员A（RHOA）是细胞运动的关键调节因子，在多种癌症中，它常因缺氧而上调。然而，其在胃癌（GC）缺氧条件下的表现仍 largely 未被探索。此外，RHOA在细胞运动中的作用在多大程度上是通过影响线粒体重塑介导的尚不清楚。在这里，我们表明GC细胞中升高的RHOA水平会引发线粒体形态变化，从管状变为与应激相关的套索状和环状，这与活性氧（ROS）增加相关。然而，经历缺氧的RHOA过表达细胞迁移增加，尽管线粒体裂变和ROS水平降低。RHO相关卷曲螺旋激酶（ROCK）抑制会损害线粒体形态变化，表明它在线粒体重塑中起作用。这些结果表明对缺氧有独特的适应性反应，其中RHOA上调增加了GC细胞的运动性并调节了线粒体可塑性。总之，RHOA介导的线粒体重塑可能是肿瘤细胞在低氧环境中适应和迁移的关键调节因子。
