A Prototypical Small‐Molecule Modulator Uncouples Mitochondria in Response to Endogenous Hydrogen Peroxide Production

McQuaker, Stephen J.; Quinlan, Casey L.; Caldwell, Stuart T.; Brand, Martin D.; Hartley, Richard C.

doi:10.1002/cbic.201300115

Cited by 22 publications

(24 citation statements)

References 36 publications

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“…8E, a decrease in uorescence intensity was observed, which could be attributed to the H 2 O 2 existing in the tumor cells. 51 Consequently, all the results demonstrated that the multianalyte CDs sensing system has good potential for the imaging of intracellular H 2 O 2 .…”

Section: Intracellular Imaging Of Fe(iii) and H 2 Omentioning

confidence: 81%

A multianalyte fluorescent carbon dots sensing system constructed based on specific recognition of Fe(iii) ions

et al. 2017

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In this research, we developed a multianalyte fluorescence sensing system through a carbon dots (CDs)-based fluorescent probe that can specifically recognize Fe(III) by fluorescence quenching. The CDs prepared using black tea by a hydrothermal method show outstanding properties like low cytotoxicity, high photostability, excellent biocompatibility, and high sensitivity. It was found that the fluorescence of CDs can be quenched by micromolar concentrations of Fe(III) in both aqueous solutions as well as living cells. It is well known that glucose can be oxidized by glucose oxidase (GOx) to release H 2 O 2 , which, in turn, can oxidize Fe(II) to Fe(III). Based on this consideration, a multianalyte sensing system was established. Therefore the quantitative analysis of Fe(III), H 2 O 2 , and glucose with detection limits of 0.25 mM, 0.82 mM, and 1.71 mM, respectively, was achieved by the simple and cost-effective multianalyte CDs sensing system constructed. The sensing system showed high photostability and negligible cytotoxicity toward HeLa cells, which enables it to be applied in the visualization of Fe(III) or H 2 O 2 in living cells. The system was further applied in the detection of Fe(III) or glucose in human serum, and satisfactory results were obtained.

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Section: Intracellular Imaging Of Fe(iii) and H 2 Omentioning

confidence: 81%

A multianalyte fluorescent carbon dots sensing system constructed based on specific recognition of Fe(iii) ions

et al. 2017

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“…For uncouplers to work safely, these compounds should cause uncoupling that increases very little as their concentration rises, potentially widening the difference between therapeutic and toxic doses and giving a wide therapeutic window (62). Recently, however, targeted uncoupling showing precise spatial and temporal control of mitochondrial function have been demonstrated, leading to the selective uncoupling of either individual or small groups of them within a cell (63,64). Such technology, if adapted to SR4 in the future, will increase its safety and potentially lower the effective maximum dose required for its cytotoxic effects on tumors.…”

Section: Discussionmentioning

confidence: 99%

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

Figarola

Singhal

Tompkins

et al. 2015

Journal of Biological Chemistry

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Mitochondrial oxidative phosphorylation produces most of the energy in aerobic cells by coupling respiration to the production of ATP. Mitochondrial uncouplers, which reduce the proton gradient across the mitochondrial inner membrane, create a futile cycle of nutrient oxidation without generating ATP. Regulation of mitochondrial dysfunction and associated cellular bioenergetics has been recently identified as a promising target for anticancer therapy. Here, we show that SR4 is a novel mitochondrial uncoupler that causes dose-dependent increase in mitochondrial respiration and dissipation of mitochondrial membrane potential in HepG2 hepatocarcinoma cells. These effects were reversed by the recoupling agent 6-ketocholestanol but not cyclosporin A and were nonexistent in mitochondrial DNA-depleted HepG2 cells. In isolated mouse liver mitochondria, SR4 similarly increased oxygen consumption independent of adenine nucleotide translocase and uncoupling proteins, decreased mitochondrial membrane potential, and promoted swelling of valinomycin-treated mitochondria in potassium acetate medium. Mitochondrial uncoupling in HepG2 cells by SR4 results in the reduction of cellular ATP production, increased ROS production, activation of the energy-sensing enzyme AMPK, and inhibition of acetyl-CoA carboxylase and mammalian target of rapamycin signaling pathways, leading to cell cycle arrest and apoptosis. Global analysis of SR4-associated differential gene expression confirms these observations, including significant induction of apoptotic genes and down-regulation of cell cycle, mitochondrial, and oxidative phosphorylation pathway transcripts at 24 h post-treatment. Collectively, our studies demonstrate that the previously reported indirect activation of AMPK and in vitro anticancer properties of SR4 as well as its beneficial effects in both animal xenograft and obese mice models could be a direct consequence of its mitochondrial uncoupling activity. Hepatocellular carcinoma (HCC)2 is the most common and severe form of liver cancer, accounting for about 80 -90% of primary liver cancers and 5% of all human cancers. More than 600,000 deaths are attributed to HCC every year with 2:1 ratio for men versus women (1, 2). HCC is a primary cancer of hepatocytes that most typically occurs in the setting of known risk factors, including cirrhosis and chronic hepatitis B virus or hepatitis C virus infections (2, 3), although recently, several lines of evidence suggest that type 2 diabetes is also an independent risk factor for HCC development (4). HCC is an aggressive tumor and represents a major health problem as its incidence is increasing. Systemic chemotherapies have proven ineffective against advanced HCC, so it typically leads to death within 6 -20 months (5). Hepatocarcinogenesis is a multistep process involving inflammation, hyperplasia, and dysplasia that finally leads to malignant transformation. In recent years, mitochondria have been found to provide a novel targeting site for new anticancer drugs (known as "mitocans") that ca...

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“…442 The compound was shown to release “free” DNP in mitochondria under the conditions of H 2 O 2 production. A similar strategy was also proposed for mitochondria-targeted “caged” DNP, activatable by light (MitoPhotoDNP, Chart 64).…”

Section: Mitochondria-targeted Bioactive Compounds As Potential Thmentioning

confidence: 99%

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Zielonka¹,

Joseph²,

et al. 2017

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Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the potentials of cell and mitochondrial membranes, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

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A Prototypical Small‐Molecule Modulator Uncouples Mitochondria in Response to Endogenous Hydrogen Peroxide Production

Cited by 22 publications

References 36 publications

A multianalyte fluorescent carbon dots sensing system constructed based on specific recognition of Fe(iii) ions

A multianalyte fluorescent carbon dots sensing system constructed based on specific recognition of Fe(iii) ions

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

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