Santidrian 2013 J Clin Invest

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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.

» PMID: 23426180 Open Access

Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, Leboeuf SE, Gay LJ, Yagi T, Felding-Habermann B (2013) J Clin Invest

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 

HRR: Oxygraph-2k