Mitochondria-targeted Triphenylamine Derivatives Activatable by Two-Photon Excitation for Triggering and Imaging Cell Apoptosis

Chennoufi, Rahima; Bougherara, Houcine; Gagey‐Eilstein, Nathalie; Dumat, Blaise; Henry, Étienne; Subra, Frédéric; Bury‐Moné, Stéphanie; Mahuteau-Betzer, Florence; Tauc, Patrick; Teulade-Fichou, Marie-Paule; Deprez, Eric

doi:10.1038/srep21458

Cited by 49 publications

(54 citation statements)

References 47 publications

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“…Recently, novel properties of two compounds, TP2Py and TP3Bzim, were revealed in living cells. In contrast to the observation in fixed cells, the initial localization of TP2Py/TP3Bzim was shown to be exclusively cytoplasmic in living cells 16 . Upon one-(visible light) or two-photon (NIR) excitation, these two compounds triggered cell death, a phenomenon mediated by ROS production and strictly dependent on TPA photoactivation 16,17 .…”

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confidence: 93%

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Interplay between Cellular Uptake, Intracellular Localization and the Cell Death Mechanism in Triphenylamine-Mediated Photoinduced Cell Death

Chennoufi

Trinh

Simon

et al. 2020

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Béatrice Rambaud 1 , patrick tauc 1 , céline frochot 3 , Marie-paule teulade-fichou 2 ✉ , florence Mahuteau-Betzer 2 ✉ & eric Deprez 1 ✉ triphenylamines (tpAs) were previously shown to trigger cell death under prolonged one-or twophoton illumination. their initial subcellular localization, before prolonged illumination, is exclusively cytoplasmic and they translocate to the nucleus upon photoactivation. However, depending on their structure, they display significant differences in terms of precise initial localization and subsequent photoinduced cell death mechanism. Here, we investigated the structural features of tpAs that influence cell death by studying a series of molecules differing by the number and chemical nature of vinyl branches. All compounds triggered cell death upon one-photon excitation, however to different extents, the nature of the electron acceptor group being determinant for the overall cell death efficiency. Photobleaching susceptibility was also an important parameter for discriminating efficient/inefficient compounds in two-photon experiments. Furthermore, the number of branches, but not their chemical nature, was crucial for determining the cellular uptake mechanism of tpAs and their intracellular fate. the uptake of all tpAs is an active endocytic process but two-and three-branch compounds are taken up via distinct endocytosis pathways, clathrin-dependent or-independent (predominantly caveolae-dependent), respectively. two-branch tpAs preferentially target mitochondria and photoinduce both apoptosis and a proper necrotic process, whereas three-branch tpAs preferentially target late endosomes and photoinduce apoptosis only.

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confidence: 93%

“…Vinyl-triphenylamine (TPA) compounds correspond to a family of fluorescent molecules exhibiting high two-photon absorption cross-sections (σ 2 ) [13][14][15][16] . Their scaffold is comprised of a triphenylamine core bearing two (TP2) or three (TP3) vinyl branches terminated by cationic electron acceptor groups, e.g.…”

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confidence: 99%

Interplay between Cellular Uptake, Intracellular Localization and the Cell Death Mechanism in Triphenylamine-Mediated Photoinduced Cell Death

Chennoufi

Trinh

Simon

et al. 2020

Sci Rep

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“…TPAs, functionalized with pyridinium (TP2Py) or benzimidazolium (TP3Bzim) cationic groups, were synthesized and tested for their phototoxic effects via two-photon NIR irradiation (Chart 84). 614 …”

Section: Mitochondria-targeted Therapeutics In the Pre-clinical Momentioning

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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“…In particular, ruptured mitochondria release large amounts of cytochrome c, AIF and Endo G and subsequently form apoptosomes, which initiate caspase and cascades and induce apoptosis [36, 37]. The key finding of the present study is that heat-induced mitochondrial dysfunction and apoptosis follows excessive production of mitochondrial ROS and enhanced mitochondrial inner membrane permeability, leading to MPT.…”

Section: Discussionmentioning

confidence: 76%

Astragaloside-IV Protects Against Heat-induced Apoptosis by Inhibiting Excessive Activation of Mitochondrial Ca2+ Uniporter

Dong

Zhang

Chen

et al. 2017

Cell Physiol Biochem

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Background: Heat causes airway damage during inhalation injury because of bronchial epithelial cell damage. Accumulating evidence shows that mitochondrial uniporter (MCU) is involved in cell damage. We investigated the MCU activity after heat treatment and assessed whether Astragaloside-IV (AS-IV) suppresses heat-induced apoptosis in bronchial epithelial cells by inhibiting the activation of the mitochondrial Ca²⁺ uniporter (MCU), mitochondrial depolarisation and reactive oxygen species (ROS) production. Methods: The bronchial epithelial cell line 16HBE14o- was heat treated, and cell apoptosis was induced in vitro and in vivo. AS-IV was inorganically administered to Wistar rats twice a day after thermal inhalation injury, and 16HBE140- cells were treated with AS-IV after incubation at 47°C for 5 min. Protein expression was determined using Western blotting and commercial kits, apoptosis with TUNEL staining, mitochondrial channel activity by patch clamp, reactive oxygen species by MitoSOX^TM fluorescence, ATP levels and enzyme activities by commercial kits as well as mitochondrial respiration and calcium by fluorescence. Results: AS-IV markedly inhibited heat-induced apoptosis, as indicated by the increased expression of the pro-apoptotic genes Bak, Bik and Bmf and increased expression of the apoptosis markers Bax, cleaved parp, cleaved caspase3 and cytochrome C. We found that MCU activation promoted mitochondrial Ca²⁺ overload, ATP depletion, mitochondrial ROS production and cytochrome c release and rapidly induced apoptosis. However, AS-IV treatment reduced excessive MCU activation and led to resistance against mitochondrial Ca²⁺ overload and excessive cytochrome C release; these effects were blocked by the MCU activator spermine. AS-IV treatment elevated ATP production and decreased ROS activity. Conclusions: MCU plays crucial roles in heat-induced mitochondrial apoptosis in 16HBE140- cells, suggesting a potential target for AS-IV treatment.

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Mitochondria-targeted Triphenylamine Derivatives Activatable by Two-Photon Excitation for Triggering and Imaging Cell Apoptosis

Cited by 49 publications

References 47 publications

Interplay between Cellular Uptake, Intracellular Localization and the Cell Death Mechanism in Triphenylamine-Mediated Photoinduced Cell Death

Interplay between Cellular Uptake, Intracellular Localization and the Cell Death Mechanism in Triphenylamine-Mediated Photoinduced Cell Death

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

Astragaloside-IV Protects Against Heat-induced Apoptosis by Inhibiting Excessive Activation of Mitochondrial Ca2+ Uniporter

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