Santidrian 2013 J Clin Invest
|Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, Leboeuf SE, Gay LJ, Yagi T, Felding-Habermann B (2013) Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest 123:1068-81.|
Abstract: 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.
• Keywords: Metastasis, NAD+/NADH redox balance, mTORC1, Autophagy
• O2k-Network Lab: US CA La Jolla Felding-Habermann B
Labels: MiParea: Respiration, mtDNA;mt-genetics, Genetic knockout;overexpression, mt-Medicine Pathology: Cancer
Organism: Human Tissue;cell: Genital Preparation: Intact cells Enzyme: Complex I, Complex III
Coupling state: ROUTINE