Exploring the inhibitor binding pocket of respiratory complex I

Fendel, Uta; Tocilescu, Maja A.; Kerscher, Stefan; Brandt, Ulrich

doi:10.1016/j.bbabio.2008.04.033

Cited by 84 publications

(71 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At the levels studied, cellular ATP levels remain constant, though there may be a non-significant transient decrease on first exposure of cells to the compounds. This contrasts strongly with the effects of rotenone, an insecticide which produces long-lasting significant decreases in ATP levels (Fendel et al 2008). These compounds appear to have a similar mode of action to metformin (Bridges et al 2014, Brunmair et al 2004, El-Mir et al 2000, Fontaine 2014, Owen et al 2000, Zhou et al 2001, the drug of choice for treating type 2 diabetes.…”

Section: Discussioncontrasting

confidence: 39%

Novel mitochondrial complex I inhibitors restore glucose-handling abilities of high-fat fed mice

Martin¹,

Leonard²,

Devine³

et al. 2016

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Metformin is the main drug of choice for treating type 2 diabetes, yet the therapeutic regimens and side effects of the compound are all undesirable and can lead to reduced compliance. The aim of this study was to elucidate the mechanism of action of two novel compounds which improved glucose handling and weight gain in mice on a high-fat diet. Wildtype C57Bl/6 male mice were fed on a high-fat diet and treated with novel, anti-diabetic compounds. Both compounds restored the glucose handling ability of these mice. At a cellular level, these compounds achieve this by inhibiting complex I activity in mitochondria, leading to AMP-activated protein kinase activation and subsequent increased glucose uptake by the cells, as measured in the mouse C2C12 muscle cell line. Based on the inhibition of NADH dehydrogenase (IC50 27µmolL−1), one of these compounds is close to a thousand fold more potent than metformin. There are no indications of off target effects. The compounds have the potential to have a greater anti-diabetic effect at a lower dose than metformin and may represent a new anti-diabetic compound class. The mechanism of action appears not to be as an insulin sensitizer but rather as an insulin substitute.

show abstract

Section: Discussioncontrasting

confidence: 39%

Novel mitochondrial complex I inhibitors restore glucose-handling abilities of high-fat fed mice

Martin¹,

Leonard²,

Devine³

et al. 2016

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

show abstract

“…As death inducers, we used amphotericin B, a polyene antibiotic often used for treatment of systemic candidiasis or aspergillosis (52); phytosphingosine, with established antifungal activity against N. crassa and Aspergillus nidulans (8,9); and the oxidative stress agent hydrogen peroxide (44). As complex I inhibitors, we employed diphenyleneiodonium (DPI), a rather nonspecific inhibitor of NADH dehydrogenases (2, 37), and piericidin A, which interferes with the ubiquinone binding site of the enzyme, as does rotenone (20,47). We used concentrations of death inhibitors that led to a visible effect on fungal growth.…”

Section: Resultsmentioning

confidence: 99%

Rotenone Enhances the Antifungal Properties of Staurosporine

et al. 2010

View full text Add to dashboard Cite

We studied staurosporine-induced cell death in the filamentous fungus Neurospora crassa. The generation of reactive oxygen species during the process appears to be an important signaling event, since addition of the antioxidant glutathione prevents the effects of staurosporine on fungal growth. Selected mutants with mutations in respiratory chain complex I are extremely sensitive to the drug, stressing the involvement of complex I in programmed cell death. Following this finding, we determined that the complex I-specific inhibitor rotenone used in combination with staurosporine results in a synergistic and specific antifungal activity, likely through a concerted action on intracellular glutathione depletion. Paradoxically, the synergistic antifungal activity of rotenone and staurosporine is observed in N. crassa complex I mutants and in Saccharomyces cerevisiae, which lacks complex I. In addition, it is not observed when other complex I inhibitors are used instead of rotenone. These results indicate that the rotenone effect is independent of complex I inhibition. The combination of rotenone and staurosporine is effective against N. crassa as well as against the common pathogens Aspergillus fumigatus and Candida albicans, pointing to its usefulness as an antifungal agent.Programmed cell death (PCD) refers to a genetically controlled process of cellular suicide initiated by endogenous or extrinsic signals. Many of the genes involved are widely conserved from unicellular to multicellular organisms (46). Apoptosis and autophagy, with its particular characteristics, have been recognized as the main categories of PCD (27). The process of PCD is crucial for the development and homeostasis of metazoan organisms and has been implicated in a number of human disorders, including cancer and neurodegenerative and infectious diseases (3,10,25,55).The participation in PCD of mitochondria, the cellular organelles responsible for the production of most cellular ATP in eukaryotes (30), has been well established. Particularly, these organelles have a central role in the intrinsic (mitochondriondependent) pathway of apoptosis, which includes production of reactive oxygen species (ROS), membrane depolarization, ultrastructural changes, and the release of cytochrome c and other proteins (18,50,55). Drugs like staurosporine (STS), an inhibitor of protein kinases, have been used to induce the mitochondrion-dependent pathway of apoptosis (24, 35). Staurosporine (48) and derivatives have been used in clinical trials for cancer therapy (63). The complex I inhibitor rotenone too has been widely used to induce PCD and also extensively applied as a pesticide (11,39,56). Thus, these types of drugs can be employed for the acquisition of fundamental knowledge and for more practical applications, like modulation of the progression of PCD.Modulation of PCD by targeting metabolic pathways involved in the process can be exploited to the benefit of human health in several very significant situations, from cancer therapy (4, 57) to the treatment of f...

show abstract

“…Overnight cultures were prepared in YPD and washed, and ϳ10 3 cells/10 l were inoculated into microtiter wells. CI to CV ETC inhibitors (Sigma-Aldrich), including rotenone (10 g/ml), C12E8 (4 g/ml), PdA (4 g/ml), TTFA (10 g/ml), antimycin A (10 g/ml), KCN (10 g/ml), and oligomycin (10 g/ml), were used alone or in combination with fluconazole (22,23). Growth was evaluated by measuring cell density (optical density at 595 nm [OD 595 ]) after 24 h of incubation at 30°C.…”

Section: Methodsmentioning

confidence: 99%

Azole Susceptibility and Transcriptome Profiling in Candida albicans Mitochondrial Electron Transport Chain Complex I Mutants

Sun

Fonzi

Chen

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

dMitochondrial dysfunction in pathogenic fungi or model yeast causes altered susceptibilities to antifungal drugs. Here we have characterized the role of mitochondrial complex I (CI) of Candida albicans in antifungal susceptibility. Inhibitors of CI to CV, except for CII, increased the susceptibility of both patient and lab isolates, even those with a resistance phenotype. In addition, in a C. albicans library of 12 CI null mutants, 10 displayed hypersusceptibility to fluconazole and were severely growth inhibited on glycerol, implying a role for each gene in cell respiration. We chose two other hypersusceptible null mutants of C. albicans, the goa1⌬ and ndh51⌬ mutants, for transcriptional profiling by RNA-Seq. Goa1p is required for CI activity, while Ndh51p is a CI subunit. RNA-Seq revealed that both the ndh51⌬ mutant and especially the goa1⌬ mutant had significant downregulation of transporter genes, including CDR1 and CDR2, which encode efflux proteins. In the goa1⌬ mutant, we noted the downregulation of genes required for the biogenesis and replication of peroxisomes, as well as metabolic pathways assigned to peroxisomes such as ␤-oxidation of fatty acids, glyoxylate bypass, and acetyl coenzyme A (acetyl-CoA) transferases that are known to shuttle acetyl-CoA between peroxisomes and mitochondria. The transcriptome profile of the ndh51⌬ mutant did not include downregulation of peroxisome genes but had, instead, extensive downregulation of the ergosterol synthesis gene family. Our data establish that cell energy is required for azole susceptibility and that downregulation of efflux genes may be an outcome of that dysfunction. However, there are mutant-specific changes that may also increase the susceptibility of both of these C. albicans mutants to azoles.

show abstract

Exploring the inhibitor binding pocket of respiratory complex I

Cited by 84 publications

References 21 publications

Novel mitochondrial complex I inhibitors restore glucose-handling abilities of high-fat fed mice

Novel mitochondrial complex I inhibitors restore glucose-handling abilities of high-fat fed mice

Rotenone Enhances the Antifungal Properties of Staurosporine

Azole Susceptibility and Transcriptome Profiling in Candida albicans Mitochondrial Electron Transport Chain Complex I Mutants

Contact Info

Product

Resources

About