Inhibitory Effects of Tannins on the NADH Dehydrogenase Activity of Bovine Heart Mitochondrial Complex I.

Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How metformin diminishes tumor growth is not fully understood. In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I.

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Association study of polymorphisms in the autosomal mitochondrial complex I subunit gene, NADH dehydrogenase (ubiquinone) flavoprotein 2, and bipolar disorder

Psychiatric Genetics ◽

10.1097/ypg.0b013e328341333f ◽

2011 ◽

Vol 21 (1) ◽

pp. 51-52 ◽

Cited By ~ 7

Author(s):

Glenn A. Doyle ◽

John P. Dahl ◽

Paul J. Bloch ◽

Andrew E. Weller ◽

Falk W. Lohoff ◽

...

Keyword(s):

Bipolar Disorder ◽

Association Study ◽

Complex I ◽

Nadh Dehydrogenase ◽

Mitochondrial Complex I ◽

Subunit Gene ◽

Mitochondrial Complex

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Inhibitory Effects of Amorphigenin on the Mitochondrial Complex I of Culex pipiens pallens Coquillett (Diptera: Culicidae)

International Journal of Molecular Sciences ◽

10.3390/ijms160819713 ◽

2015 ◽

Vol 16 (8) ◽

pp. 19713-19727 ◽

Cited By ~ 2

Author(s):

Mingshan Ji ◽

Yaping Liang ◽

Zumin Gu ◽

Xiuwei Li

Keyword(s):

Complex I ◽

Culex Pipiens ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Inhibitory Effects ◽

Culex Pipiens Pallens ◽

Pipiens Pallens

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Synthesis of pyranicin and its deoxygenated analogues and their inhibitory action with bovine heart mitochondrial complex I

Tetrahedron ◽

10.1016/j.tet.2008.06.028 ◽

2008 ◽

Vol 64 (33) ◽

pp. 7695-7703 ◽

Cited By ~ 11

Author(s):

Shin-ichi Furuhata ◽

Yasunao Hattori ◽

Motonori Okajima ◽

Hiroyuki Konno ◽

Masato Abe ◽

...

Keyword(s):

Complex I ◽

Inhibitory Action ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Bovine Heart

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Chemical Modification of the Mitochondrial Complex I Inhibitor 1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline: Synthesis and Evaluation of N-Alkanoyl Derivatives

Zeitschrift für Naturforschung C ◽

10.1515/znc-2000-7-822 ◽

2000 ◽

Vol 55 (7-8) ◽

pp. 620-630 ◽

Cited By ~ 1

Author(s):

Gerhard Bringmann ◽

Doris Feineis ◽

Ralf God ◽

Ralph Brückner ◽

Jens Achim-Protzen ◽

...

Keyword(s):

Complex I ◽

Mitochondrial Complex I ◽

Mitochondrial Complex ◽

Inhibitory Effects ◽

Trichloromethyl Group ◽

Hydrophobic Portion ◽

Complex I Activity ◽

Mitochondrial Complex I Inhibitor ◽

Lipophilic Character

Abstract Several N-alkanoyl derivatives (4-9 and 13-16) of the potent mitochondrial complex I inhibitor TaClo (1-trichlorom ethyl-1,2,3,4-tetrahydro-β-carboline, 2) have been synthesized in order to elucidate the role of hydrophobic portion in the inhibitory action. Using rat brain homogenates or submitochondrial particles, the inhibitory effects of these compounds towards NADH-ubiquinone reductase (complex I) activity indeed appeared to correlate quite strongly with their lipophilic character. An X-ray structure analysis, exemplarily performed for N-acetyl-TaClo (4), revealed the N-substituent of such chlorinated agents to be dramatically pushed out of the β-carboline ring ‘plane’ due to the high steric demand of the huge trichloromethyl group at C-1.

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