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

• Published in: The Journal of clinical investigation 2013-03, Vol.123 (3), p.1068-1081
• Main Authors: Santidrian, Antonio F, Matsuno-Yagi, Akemi, Ritland, Melissa, Seo, Byoung B, LeBoeuf, Sarah E, Gay, Laurie J, Yagi, Takao, Felding-Habermann, Brunhilde
• Format: Article
• Language: English
• Subjects: Acrylamides - pharmacology; Animals; Autophagy; Autophagy-Related Protein 5; Biomedical research; Brain Neoplasms - metabolism; Brain Neoplasms - secondary; Breast cancer; Cell Line, Tumor; Cell Proliferation; Cytokines - antagonists & inhibitors; Cytokines - metabolism; Disease Progression; Electron Transport Complex I - biosynthesis; Electron Transport Complex I - physiology; Female; Gene Knockdown Techniques; Humans; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred BALB C; Mice, SCID; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mitochondria - metabolism; Multiprotein Complexes; NAD - metabolism; NAD - physiology; Neoplasm Transplantation; Niacin - pharmacology; Niacinamide - pharmacology; Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors; Nicotinamide Phosphoribosyltransferase - metabolism; Piperidines - pharmacology; Protein Transport; Proteins - metabolism; Recombinant Proteins - biosynthesis; Saccharomyces cerevisiae Proteins - biosynthesis; Saccharomyces cerevisiae Proteins - physiology; TOR Serine-Threonine Kinases
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci64264

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, mTORC1 activity, and autophagy. Conversely, nonlethal reduction of NAD+ levels by interfering 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.