Mitochondrial complex I activity and NAD+/NADH... : Journal of Clinical Investigation (original) (raw)

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

Antonio F. Santidrian
Akemi Matsuno-Yagi
Melissa Ritland
Byoung B. Seo
Sarah E. LeBoeuf
Laurie J. Gay
Takao Yagi
Brunhilde Felding-Habermann

Journal of Clinical Investigation

123

(

)

1068

1081

March 1, 2013

| 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.