Mitochondrial ROS1 Increases Mitochondrial Fission and Respiration in Oral Squamous Cancer Carcinoma

SIMPLE SUMMARY: The clinical efficacy of anti-epidermal growth factor receptor (EGFR) antibody cetuximab for oral squamous cell carcinomas (OSCCs) is low. We previously reported that an increased oncogenic ROS proto-oncogene 1 (ROS1) is responsible for the invasiveness and metastasis of OSCC. This study demonstrates for the first time that ROS1, a receptor tyrosine kinase, can localize to mitochondria. Mitochondrial ROS1 in the highly invasive OSCC promotes mitochondrial fission, enhances mitochondrial oxidative phosphorylation and ATP production but reduces mitochondrial biogenesis. These findings highlight the novel function of ROS1 in mitochondrial morphogenesis and metabolic adaptation to promote OSCC invasiveness. ABSTRACT: Increased ROS proto-oncogene 1 (ROS1) expression has been implicated in the invasiveness of human oral squamous cell carcinoma (OSCC). The cellular distribution of ROS1 has long-been assumed at the plasma membrane. However, a previous work reported a differential cellular distribution of mutant ROS1 derived from chromosomal translocation, resulting in increased carcinogenesis. We thus hypothesized that cellular distribution of upregulated ROS1 in OSCC may correlate with invasiveness. We found that ROS1 can localize to mitochondria in the highly invasive OSCC and identified a mitochondria-targeting signal sequence in ROS1. We also demonstrated that ROS1 targeting to mitochondria is required for mitochondrial fission phenotype in the highly invasive OSCC cells. OSCC cells expressing high levels of ROS1 consumed more oxygen and had increased levels of cellular ATP levels. Our results also revealed that ROS1 regulates mitochondrial biogenesis and cellular metabolic plasticity. Together, these findings demonstrate that ROS1 targeting to mitochondria enhances OSCC invasion through regulating mitochondrial morphogenesis and cellular respiratory.