Mitochondria-targeted dodecyltriphenylphosphonium (C12TPP) combats high-fat-diet-induced obesity in mice

Kalinovich, Anastasia V.; Mattsson, Charlotte L.; Youssef, Mervat; Petrovič, Nataša; Ost, Mario; Vp, Skulachev; Shabalina, Irina G.

doi:10.1038/ijo.2016.146

Cited by 23 publications

(23 citation statements)

References 58 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…437 In fact, TPP + -C 12 was shown to combat high-fat-diet-induced obesity in mice. 440 Several attempts were made to covalently conjugate uncoupling agents to the mitochondria-targeting moiety, in order to improve their efficiency and selectivity and decrease the potential toxicity.…”

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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…SkQ1 was further investigated as mitochondria-targeted antioxidant for potential treatment of various age-related diseases, such as Alzheimer's disease [31] or retinopathy [32,33]. Furthermore, a recent study demonstrated that the mitochondrial-targeted C 12 TPP effectively increased oxygen consumption in isolated brown-fat mitochondria, independent of UCP1, and abolished diet-induced obesity in mice by reducing food intake, increasing the resting metabolic rate and overall fatty acid oxidation [34]. In addition, Rhodamine 19 butyl ester (C 4 R1), a short-chain alkyl derivative of Rhodamine 19, was found to decrease the membrane potential and stimulate respiration of isolated liver mitochondria as well as reduce oxidative stress induced by brain ischemia and reperfusion in rats [35].…”

Section: Next Generation Chemical Uncouplersmentioning

confidence: 99%

“…Moreover, in the last decade research focused intensively on the induction of endogenous UCP1 in white adipose tissue depots, also called the "browning" of white fat, and the effects on metabolic health [56,62]. Abbreviations: BAM15, N 5 ,N 6 -bis(2-Fluorophenyl)-oxadiazolo-pyrazine-5,6-diamine [37]; CRMP, controlledreleased mitochondrial protonophore [44]; C 4 R1, Rhodamine 19 butyl ester [36]; C1, nomenclature not defined [38], CZ5, nomenclature not defined [39]; C 12 TPP, dodecyltriphenylphosphonium [34]; FDA, US Food and Drug Administration; DNP, 2,4-dinitrophenol; DNPME, DNP-methylethyl [43]; NEN, niclosamide ethanolamine salt [41]; SkQ1, 10-(6´-plastoquinonyl) decyltriphenylphosphonium) [30]; UCP1, uncoupling protein 1. See text for further details.…”

Section: Acknowledgementsmentioning

confidence: 99%

Targeted mitochondrial uncoupling beyond UCP1 – The fine line between death and metabolic health

2017

View full text Add to dashboard Cite

In the early 1930s, the chemical uncoupling agent 2,4-dinitrophenol (DNP) was promoted for the very first time as a powerful and effective weight loss pill but quickly withdrawn from the market due to its lack of tissue-selectivity with resulting dangerous side effects, including hyperthermia and death. Today, novel mitochondria- or tissue-targeted chemical uncouplers with higher safety and therapeutic values are under investigation in order to tackle obesity, diabetes and fatty liver disease. Moreover, in the past 20 years, transgenic mouse models were generated to understand the molecular and metabolic consequences of targeted uncoupling, expressing functional uncoupling protein 1 (UCP1) ectopically in white adipose tissue or skeletal muscle. Similar to the action of chemical mitochondrial uncouplers, UCP1 protein dissipates the proton gradient across the inner mitochondrial membrane, thus allowing maximum activity of the respiratory chain and compensatory increase in oxygen consumption, uncoupled from ATP synthesis. Consequently, targeted mitochondrial uncoupling in adipose tissue and skeletal muscle of UCP1-transgenic mice increased substrate metabolism and ameliorates obesity, hypertriglyceridemia and insulin resistance. Further, muscle-specific decrease in mitochondrial efficiency promotes a cell-autonomous and cell-non-autonomous adaptive metabolic remodeling with increased oxidative stress tolerance. This review provides an overview of novel chemical uncouplers as well as the metabolic consequences and adaptive processes of targeted mitochondrial uncoupling on metabolic health and survival.

show abstract

“…Dodecyltriphenylphosphonium (C 12 TPP) has been found to act as an uncoupler, being co-transported with a free fatty acid 23 . The uncoupling activity allows to use this chemical as an anti-obesity drug in murine models 24 . Moreover, lipophilic cations including C 12 TPP appear to be competitive inhibitors of MDR 25 – 27 .…”

Section: Introductionmentioning

confidence: 99%

Penetrating cations induce pleiotropic drug resistance in yeast

Galkina

Besedina

Zinovkin

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Substrates of pleiotropic drug resistance (PDR) transporters can induce the expression of corresponding transporter genes by binding to their transcription factors. Penetrating cations are substrates of PDR transporters and theoretically may also activate the expression of transporter genes. However, the accumulation of penetrating cations inside mitochondria may prevent the sensing of these molecules. Thus, whether penetrating cations induce PDR is unclear. Using Saccharomyces cerevisiae as a model, we studied the effects of penetrating cations on the activation of PDR. We found that the lipophilic cation dodecyltriphenylphosphonium (C12TPP) induced the expression of the plasma membrane PDR transporter genes PDR5, SNQ2 and YOR1. Moreover, a 1-hour incubation with C12TPP increased the concentration of Pdr5p and Snq2p and prevented the accumulation of the PDR transporter substrate Nile red. The transcription factor PDR1 was required to mediate these effects, while PDR3 was dispensable. The deletion of the YAP1 or RTG2 genes encoding components of the mitochondria-to-nucleus signalling pathway did not prevent the C12TPP-induced increase in Pdr5-GFP. Taken together, our data suggest (i) that the sequestration of lipophilic cations inside mitochondria does not significantly inhibit sensing by PDR activators and (ii) that the activation mechanisms do not require mitochondria as a signalling module.

show abstract

Mitochondria-targeted dodecyltriphenylphosphonium (C12TPP) combats high-fat-diet-induced obesity in mice

Cited by 23 publications

References 58 publications

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

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

Targeted mitochondrial uncoupling beyond UCP1 – The fine line between death and metabolic health

Penetrating cations induce pleiotropic drug resistance in yeast

Contact Info

Product

Resources

About