Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression

Santidrian, Antonio F.; Matsuno-Yagi, Akemi; Ritiand, Melissa; Seo, Byoung B.; LeBoeuf, Sarah E.; Gay, Laurie J.; Yagi, Takao; Felding-Habermann, Brunhilde
March 2013
Journal of Clinical Investigation;Mar2013, Vol. 123 Issue 3, p1068
Academic Journal
Despite advances in clinical therapy, metastasis remains the leading cause of death in breast cancer patients. Mutations in mitochondrial DNA, including those affecting complex I and oxidative phosphorylation, are found in breast tumors and could facilitate metastasis. This study identifies mitochondrial complex I as critical for defining an aggressive phenotype in breast cancer cells. Specific enhancement of mitochondrial complex I activity inhibited tumor growth and metastasis through regulation of the tumor cell NAD+/NADH redox balance, mTORCl activity, and autophagy. Conversely, nonlethal reduction of NAD+ levels by inter-fering with nicotinamide phosphoribosyltransferase expression rendered tumor cells more aggressive and increased metastasis. The results translate into a new therapeutic strategy: enhancement of the NAD+/NADH balance through treatment with NAD+ precursors inhibited metastasis in xenograft models, increased animal survival, and strongly interfered with oncogene-driven breast cancer progression in the MMTV-PyMT mouse model. Thus, aberration in mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells, while therapeutic normalization of the NAD+/NADH balance can inhibit metastasis and prevent disease progression.


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