Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine.
Bottom Line: However, the effect of LND on central energy metabolism has never been fully characterized.The ability of LND to promote cell death was potentiated by its suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation.Using stable isotope tracers in combination with isotopologue analysis, we showed that LND increased glutaminolysis but decreased reductive carboxylation of glutamine-derived α-ketoglutarate.
Affiliation: From the Penn Superfund Research and Training Program Center, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics and.Show MeSH
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Mentions: To rule out the possibility that the inhibition of the succinate dehydrogenase activity of complex II by LND was an indirect effect resulting from metabolic alterations in the cytosol, we examined the conversion of succinate to fumarate using isolated mitochondria. Importantly, the utilization of isolated mitochondria reduces interference of cytoplasmic metabolites and enzymes. To interrogate the specific action of complex II, isolated mitochondria were incubated with 5 mm [13C4]succinate. The generation of [13C4]fumarate, [13C4]malate, and [13C4]citrate was quantified to assess succinate metabolism. Within 30 min of incubation, 106 nmol of [13C4]fumarate and 232 nmol of [13C4]malate were generated from 60 μg of mitochondria with vehicle treatment. No heavy labeled citrate was detected, most likely due to the lack of external acetyl-CoA supply. The addition of LND inhibited the production of [13C4]fumarate and [13C4]malate (Fig. 2, A and B). 150 μm LND inhibited ∼40% of fumarate and 50% of malate production. The extent of inhibition caused by LND was similar to that of 3-NPA at various concentrations, whereas TTFA was a more potent inhibitor of complex II (Fig. 2, A and B). Overall, our observations suggest that the inhibition of complex II activity by LND is independent of lactate accumulation or other metabolic changes in the cytosol.
Affiliation: From the Penn Superfund Research and Training Program Center, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics and.