earticle

영어

Tumor cells express altered metabolic activities often linked to mitochondrial dysfunction. Such mitochondrial defects can inhibit oxidative phosphorylation, change the cellular redox status (NAD+/NADH), increase production of reactive oxygen species (ROS), and cause DNA damage that further supports tumorigenesis and a metastatic phenotype1,2. Mitochondrial Complex I (NADH dehydrogenase) is a major site of ROS production in mitochondria and regulator of the NAD+/NADH ratio. This study is focused on mitochondrial complex I as a possible modulator of tumorigenesis and progression in breast cancer. We used NADH dehydrogenase from yeast, called NDI1, to augment complexI activity in metastatic human breast cancer cells. We followed NDI1 functionality and impact on tumor cell behavior in vitro and tumor progression in vivo. Augmentation of NADH dehydrogenase activity through NDI1 resulted in an enhanced NAD+/NADH ratio and slight inhibition of ROS production. Importantly, NDI1 expression inhibited metastasis and tumor growth in the mammary fad pad of immune deficient mice, as seen by non-invasive bioluminescence imaging and histology. The mechanisms involve NDI1-induced inhibition of the AKT/mTOR survival pathway and autophagy stimulation. Knock-down of ATG5 partially reversed the anti-metastatic effect of NDI1, demonstrating that enhancement of autophagy is responsible for NDI1-mediated inhibition of breast cancer spreading. The results indicate that mitochondrial complex I activity can drastically impact tumorigenesis and metastasis in breast cancer, and that augmentation of complex I function through NDI1 can inhibit tumor formation and cancer progression through NAD+/NADH ratio modulation.