Trichomonas hydrogenosomes contain the NADH dehydrogenase module of mitochondrial complex I

Nature ◽  
2004 ◽  
Vol 432 (7017) ◽  
pp. 618-622 ◽  
Author(s):  
Ivan Hrdy ◽  
Robert P. Hirt ◽  
Pavel Dolezal ◽  
Lucie Bardonová ◽  
Peter G. Foster ◽  
...  
eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
William W Wheaton ◽  
Samuel E Weinberg ◽  
Robert B Hamanaka ◽  
Saul Soberanes ◽  
Lucas B Sullivan ◽  
...  

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.


2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yao-Peng Xue ◽  
Mou-Chieh Kao ◽  
Chung-Yu Lan

Abstract The emergence of drug-resistant fungal pathogens is becoming increasingly serious due to overuse of antifungals. Antimicrobial peptides have potent activity against a broad spectrum of pathogens, including fungi, and are considered a potential new class of antifungals. In this study, we examined the activities of the newly designed peptides P-113Du and P-113Tri, together with their parental peptide P-113, against the human fungal pathogen Candida albicans. The results showed that these peptides inhibit mitochondrial complex I, specifically NADH dehydrogenase, of the electron transport chain. Moreover, P-113Du and P-113Tri also block alternative NADH dehydrogenases. Currently, most inhibitors of the mitochondrial complex I are small molecules or artificially-designed antibodies. Here, we demonstrated novel functions of antimicrobial peptides in inhibiting the mitochondrial complex I of C. albicans, providing insight in the development of new antifungal agents.


Author(s):  
Niklas Klusch ◽  
Jennifer Senkler ◽  
Özkan Yildiz ◽  
Werner Kühlbrandt ◽  
Hans-Peter Braun

Abstract Mitochondrial complex I is the main site for electron transfer to the respiratory chain and generates much of the proton gradient across the inner mitochondrial membrane. Complex I is composed of two arms, which form a conserved L-shape. We report the structures of the intact, 47-subunit mitochondrial complex I from Arabidopsis thaliana and the 51-subunit complex I from the green alga Polytomella sp., both at around 2.9 Å resolution. In both complexes, a heterotrimeric γ-carbonic anhydrase domain is attached to the membrane arm on the matrix side. Two states are resolved in A. thaliana complex I, with different angles between the two arms and different conformations of the ND1 (NADH dehydrogenase subunit 1) loop near the quinol binding site. The angle appears to depend on a bridge domain, which links the peripheral arm to the membrane arm and includes an unusual ferredoxin. We propose that the bridge domain participates in regulating the activity of plant complex I.


1993 ◽  
Vol 21 (4) ◽  
pp. 998-1001 ◽  
Author(s):  
Hans Leif ◽  
Uwe Weidner ◽  
Annette Berger ◽  
Volker Spehr ◽  
Matthias Braun ◽  
...  

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