Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression
Antonio F. Santidrian, … , Takao Yagi, Brunhilde Felding-Habermann
Antonio F. Santidrian, … , Takao Yagi, Brunhilde Felding-Habermann
Published February 15, 2013
Citation Information: J Clin Invest. 2013;123(3):1068-1081. https://doi.org/10.1172/JCI64264.
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Research Article Oncology

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

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.

Authors

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

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Mitochondrial complex I activity modulates tumor growth and metastasis.

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Mitochondrial complex I activity modulates tumor growth and metastasis. ...
(A) Ndi1 expression inhibited mammary fat pad tumor growth of MDA-MB-435 and MDA-MB-231 cells. Control cells were transduced with empty vector (n = 6). (B) Ndi1 expression inhibited lung colonization (experimental metastasis) by MDA-MB-435 or MDA-MB-231 cells after i.v. injection. Control cells were transduced with empty vector (n = 6). (C) Ndi1 expression inhibited multiorgan experimental metastasis, as indicated by noninvasive bioluminescence imaging 7 weeks after i.v. injection of 2.5 × 105 MDA-MB-435 control or Ndi1-expressing cells (n = 5). (D) Knockdown of complex I subunit NFUFV1 expression inhibited complex I activity and respiratory capacity in MDA-MB-435 cells. NDUFV1-knockdown (shV1) and control (shCT) cells were compared. Complex I was immunocaptured from cell lysates, analyzed based on oxidation of NADH to NAD+, expressed as mean OD/min/mg protein (n = 3). Routine mitochondrial respiration, corrected for residual oxygen consumption due to oxidative side reactions, was measured in intact MDA-MB-435 control and NDUFV1-knockdown cells by high-resolution respirometry (n = 3). (E) NDUFV1 knockdown increased lung colonization activity in MDA-MB-435 cells. NDUFV1-knockdown and control cells were compared (n = 8). Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, nonparametric Mann-Whitney test (A, B, and E) or unpaired 2-tailed Student’s t test (D).