Mitochondrial complex I modulation of cellular NAD+/NADH regulates mTOR, autophagy and breast cancer progression

抄録

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 phenotype. Mitochondrial Complex I is a major site of ROS production in mitochondria and regulator of the NAD+/NADH ratio. Our 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 specifically augment complex I activity in metastatic human breast cancer cells. We followed Ndi1 functionality and impact on tumor cell behavior in vitro and tumor progression in vivo. We found that NAD+/NADH regulation by complex I activity modulated the mTOR survival pathway and autophagy stimulation. The results demonstrate that enhancement of autophagy is responsible for the inhibition of breast cancer spreading by normalizing complex I activity. These results provide definitive evidence that specific modulation of breast cancer cell complex I activity can significantly alter tumor progression and metastatic activity through modulation of the NAD+/NADH ratio and mTOR/autophagy pathways. Therefore, complex I mutations found in primary tumors of breast cancer patients could play a key role in breast cancer progression. Mitochondria play an important role in sperm cell maturation and function and bovine sperm cell was treated with mitochondria complex I inhibitor. We will examine suppression of the ROS in the bovine sperm mitochondria by NDI1 infection.