Water-Soluble Coenzyme Q10 Inhibits Nuclear Translocation of Apoptosis Inducing Factor and Cell Death Caused by Mitochondrial Complex I Inhibition

Cancer cells generally rely mostly on glycolysis rather than oxidative phosphorylation (OXPHOS) for ATP production. In fact, they are particularly sensitive to glycolysis inhibition and glucose depletion. On the other hand mitochondrial dysfunctions, involved in the onset of the Warburg effect, are sometimes also associated with the resistance to apoptosis that characterizes cancer cells. Therefore, combined treatments targeting both glycolysis and mitochondria function, exploiting peculiar tumor features, might be lethal for cancer cells. In this study, we show that glucose deprivation and mitochondrial Complex I inhibitors synergize in inducing cancer cell death. In particular, our results reveal that low doses of Complex I inhibitors, ineffective on immortalized cells and in high glucose growth, become specifically cytotoxic on cancer cells deprived of glucose. Importantly, the cytotoxic effect of the inhibitors on cancer cells is strongly enhanced by forskolin, a PKA pathway activator, that we have previously shown to stimulate OXPHOS. Taken together, we demonstrate that induction in cancer cells of a switch from a glycolytic to a more respirative metabolism, obtained by glucose depletion or mitochondrial activity stimulation, strongly increases their sensitivity to low doses of mitochondrial Complex I inhibitors. Our findings might be a valuable approach to eradicate cancer cells.

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Mitochondrial complex I inhibitors, acetogenins, induce HepG2 cell death through the induction of the complete apoptotic mitochondrial pathway

Journal of Bioenergetics and Biomembranes ◽

10.1007/s10863-012-9489-1 ◽

2012 ◽

Vol 45 (1-2) ◽

pp. 153-164 ◽

Cited By ~ 21

Author(s):

Nuria de Pedro ◽

Bastien Cautain ◽

Angeles Melguizo ◽

Francisca Vicente ◽

Olga Genilloud ◽

...

Keyword(s):

Cell Death ◽

Hepg2 Cell ◽

Complex I ◽

Mitochondrial Pathway ◽

Mitochondrial Complex I ◽

Mitochondrial Complex

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Structure–function relationships in mitochondrial complex I of the strictly aerobic yeast Yarrowia lipolytica

Biochemical Society Transactions ◽

10.1042/bst0330840 ◽

2005 ◽

Vol 33 (4) ◽

pp. 840-844 ◽

Cited By ~ 15

Author(s):

U. Brandt ◽

A. Abdrakhmanova ◽

V. Zickermann ◽

A. Galkin ◽

S. Dröse ◽

...

Keyword(s):

Structure Function ◽

Yarrowia Lipolytica ◽

Complex I ◽

Critical Role ◽

Water Soluble ◽

Mitochondrial Complex I ◽

Strictly Aerobic ◽

Mitochondrial Complex ◽

Catalytic Core ◽

Yeast Yarrowia Lipolytica

The obligate aerobic yeast Yarrowia lipolytica has been established as a powerful model system for the analysis of mitochondrial complex I. Using a combination of genomic and proteomic approaches, a total of 37 subunits was identified. Several of the accessory subunits are predicted to be STMD (single transmembrane domain) proteins. Site-directed mutagenesis of Y. lipolytica complex I has provided strong evidence that a significant part of the ubiquinone reducing catalytic core resides in the 49 kDa and PSST subunits and can be modelled using X-ray structures of distantly related enzymes, i.e. water-soluble [NiFe] hydrogenases from Desulfovibrio spp. Iron–sulphur cluster N2, which is related to the hydrogenase proximal cluster, is directly involved in quinone reduction. Mutagenesis of His226 and Arg141 of the 49 kDa subunit provided detailed insight into the structure–function relationships around cluster N2. Overall, our findings suggest that proton pumping by complex I employs long-range conformational interactions and ubiquinone intermediates play a critical role in this mechanism.

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