ATP/ADP turnover and import of glycolytic ATP into mitochondria in cancer cells is independent of the adenine nucleotide translocator.

Maldonado, Eduardo N.; DeHart, David N.; Patnaik, Jyoti; Klatt, Sandra C.; Göõz, Monika; Lemasters, John J.

doi:10.1074/jbc.a116.734814

Cited by 15 publications

(18 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a collection of 99 feeding observations of Conuropsis, the highest plant intake (n = 17) corresponded in fact to cockleburs [4]. CAT inhibits the function of four mitochondrial ATP transporters (ANT1, ANT2, ANT3, and ANT4; encoded by SLC25A4, SLC25A5, SLC25A6, and SLC25A31, respectively), which is lethal [26,27]. We next explored these genes further by comparing them against their orthologs in other available avian genomes, including one recently generated dataset representing 363 species spanning nearly all avian families [28].…”

Section: Adaptation To Toxic Dietmentioning

confidence: 99%

Evolutionary History, Genomic Adaptation to Toxic Diet, and Extinction of the Carolina Parakeet

et al. 2020

View full text Add to dashboard Cite

Section: Adaptation To Toxic Dietmentioning

confidence: 99%

Evolutionary History, Genomic Adaptation to Toxic Diet, and Extinction of the Carolina Parakeet

et al. 2020

View full text Add to dashboard Cite

“…TMRM fluorescence and NADH autofluorescence were imaged by a Zeiss LSM 880 NLO inverted laser-scanning confocal microscope (Carl Zeiss, Oberkochen, Germany) using a 363 1.4 numerical aperture plan-apochromat oil immersion lens. TMRM and NADH intensity were quantified using Zeiss Zen and Photoshop CS4 software (Adobe Systems, San Jose, CA, USA) after subtraction of background fluorescence as previously described in Maldonado et al (22). Fluorescent polystyrene microspheres (4 mm) (MultiSpeck Multispectral Fluorescence Microscopy Standards Kit, M-7901; Thermo Fisher Scientific) were used as fiducial markers.…”

Section: Confocal Microscopymentioning

confidence: 99%

“…The electron transport chain pumps protons into the intermembrane space at complexes I, III, and IV to produce a proton motive force further used by the ATP F 1 -F 0 synthase to generate ATP from ADP and P i . The higher concentration of protons in the intermembrane space relative to that of the matrix form the negative mitochondrial membrane potential (DC), a useful readout to follow changes in mitochondrial metabolism in intact cells (21)(22)(23)(24). The relative contribution of oxphos and glycolysis, genetically determined, vary substantially over time depending on multiple nongenetic factors.…”

mentioning

confidence: 99%

Statin‐dependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content

et al. 2019

Self Cite

View full text Add to dashboard Cite

Statins, widely used to treat hypercholesterolemia, inhibit the 3‐hydroxy‐3‐methylglutary1‐coenzyme A reductase, the rate‐limiting enzyme of de novo cholesterol (Chol) synthesis. Statins have been also reported to slow tumor progression. In cancer cells, ATP is generated both by glycolysis and oxidative phosphorylation. Mitochondrial membrane potential (ΔΨ), a readout of mitochondrial metabolism, is sustained by the oxidation of respiratory substrates in the Krebs cycle to generate NADH and flavin adenine dinucleotide, which are further oxidized by the respiratory chain. Here, we studied the short‐term effects of statins (3–24 h) on mitochondrial metabolism on cancer cells. Lovastatin (LOV) and simvastatin (SIM) increased in HepG2 and Huh7 human hepatocarcinoma cells and HCC4006 human lung adenocarcinoma cells. Mitochondrial hyperpolarization after LOV and SIM was dose and time dependent. Maximal increase in ΔΨ occurred at 10 µM and 24 h for both statins. The structurally unrelated atorvastatin also hyperpolarized mitochondria in HepG2 cells. Cellular and mitochondrial Chol remained unchanged after SIM. Both LOV and SIM decreased basal respiration, ATP‐linked respiration, and ATP production. LOV and SIM did not change the rate of lactic acid production. In summary, statins modulate mitochondrial metabolism in cancer cells independently of the Chol content in cellular membranes without affecting glycolysis.—Christie, C. F., Fang, D., Hunt, E. G., Morris, M. E., Rovini, A., Heslop, K. A., Beeson, G. C., Beeson, C. C., Maldonado, E. N. Statin‐dependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content. FASEB J. 33, 8186–8201 (2019). http://www.fasebj.org

show abstract

“…Although prior work has implicated ANT2 42,55,56 and TRAP1 50 as potential anti-cancer targets in leukemia, we present for the rst time here a potential mechanism for their coordinated regulation of leukemic cell metabolism. Speci cally, our ndings inform a model of leukemia bioenergetics in which decreased ANT1 and increased ANT2 favors the uptake of extra-mitochondrial ATP into the matrix space.…”

Section: Discussionmentioning

confidence: 85%

“…Given that ATP free energy was required to induce ETS ux inhibition, we hypothesized that this effect may be mediated by ATP transport into the matrix, facilitated by enhanced ANT2 expression in leukemia 41 . To test this hypothesis, FCCP-supported respiration was assessed in energized, permeabilized MV-4-11 and HL-60 cells exposed to ΔG ATP of -61.49 kJ/mol in the absence and presence of the ANT inhibitor carboxyatractyloside (CAT) 42 . Consistent with our prior ndings, the addition of FCCP in the presence of ΔG ATP was incapable of restoring ux to levels obtained with minimal ATP free energy in leukemia ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Intrinsic oxidative phosphorylation limitations underlie cellular bioenergetics in leukemia.

Nelson

McLaughlin

Hagen

et al. 2020

Preprint

View full text Add to dashboard Cite

Currently there is great interest in developing cytotoxic pharmacotherapies that disrupt mitochondrial energy transduction in cancer. Given that mitochondria are critical to mammalian energy homeostasis, clinical success of a given therapeutic will undoubtedly hinge upon its cancer cell selectivity. That said, how the mitochondrial network is intrinsically remodeled to drive/enable the cancer phenotype remains a biological black box, largely due to limitations in analytical approaches. Herein, we leveraged an in-house diagnostic biochemical workflow to comprehensively evaluate mitochondrial bioenergetic efficiency and capacity in human leukemia. Using this platform, we provide direct evidence that despite minimal changes in absolute respiratory kinetics, leukemic mitochondria are hallmarked by intrinsic limitations in oxidative phosphorylation (OXPHOS) that constrain the network’s ability to contribute to cellular ATP free energy (i.e, ΔGATP) charge. Together, these findings link accelerated oxidative metabolism in leukemia to intrinsic OXPHOS deficiency and provide proof-of-concept that restoring, rather than disrupting, OXPHOS across the leukemic mitochondrial network may represent an untapped, but highly feasible, therapeutic avenue.

show abstract

ATP/ADP turnover and import of glycolytic ATP into mitochondria in cancer cells is independent of the adenine nucleotide translocator.

Cited by 15 publications

References 0 publications

Evolutionary History, Genomic Adaptation to Toxic Diet, and Extinction of the Carolina Parakeet

Evolutionary History, Genomic Adaptation to Toxic Diet, and Extinction of the Carolina Parakeet

Statin‐dependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content

Intrinsic oxidative phosphorylation limitations underlie cellular bioenergetics in leukemia.

Contact Info

Product

Resources

About