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.

본 연구는 체외성숙 배지에 첨가하는 PVP의 농도, EGF, cysteine 및 PVP의 단독 또는 혼합첨가가 한우 체외수정란의 체외발생에 미치는 영향을 검토하였다. 체외성숙 배지에 PVP의 첨가농도(0.1~3.0%)에 따른 분할율은 차이가 없었으나, 배반포 발달율은 0.5% PVP 첨가군이 가장 높았다(P<0.05). PVP, EGF 및 cysteine의 단독 및 혼합 첨가에 따른 분할율은 cysteine 단독첨가군이 높았으나(P<0.05), 배반포 발달율은 차이가 없었다. Inner cell mass 수는 대조군과 cysteine 첨가군이 PVP 첨가군에 비하여 유의하게 높았고(P<0.05), 총 세포수도 cysteine 첨가군에서 가장 높았다. 수정란이식 결과는 대조군, EGF, cysteine 및 EGF+cysteine 군의 임신율은 46.1~63.6%로서 비슷하였으나, PVP 첨가군은 10%로서 다른 군에 비하여 유의하게 낮았다(P<0.05). 본 연구 결과는 체외성숙 배지에 PVP의 첨가로 배 발생은 가능하지만, 세포의 품질에는 악영향을 미치는 것을 보여준다.