Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition
Pioglitazone (PIO) is an insulin-sensitizing antidiabetic drug, which normalizes glucose and lipid metabolism but may provoke heart and liver failure and chronic kidney diseases. Both therapeutic and adverse effects of PIO can be accomplished through mitochondrial targets. Here, we explored the capa...
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MDPI AG
2021-10-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/10/1045 |
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| author | Ekaterina S. Kharechkina Anna B. Nikiforova Konstantin N. Belosludtsev Tatyana I. Rokitskaya Yuri N. Antonenko Alexey G. Kruglov |
| author_facet | Ekaterina S. Kharechkina Anna B. Nikiforova Konstantin N. Belosludtsev Tatyana I. Rokitskaya Yuri N. Antonenko Alexey G. Kruglov |
| author_sort | Ekaterina S. Kharechkina |
| collection | DOAJ |
| description | Pioglitazone (PIO) is an insulin-sensitizing antidiabetic drug, which normalizes glucose and lipid metabolism but may provoke heart and liver failure and chronic kidney diseases. Both therapeutic and adverse effects of PIO can be accomplished through mitochondrial targets. Here, we explored the capability of PIO to modulate the mitochondrial membrane potential (ΔΨ<sub>m</sub>) and the permeability transition pore (mPTP) opening in different models in vitro. ΔΨ<sub>m</sub> was measured using tetraphenylphosphonium and the fluorescent dye rhodamine 123. The coupling of oxidative phosphorylation was estimated polarographically. The transport of ions and solutes across membranes was registered by potentiometric and spectral techniques. We found that PIO decreased ΔΨ<sub>m</sub> in isolated mitochondria and intact thymocytes and the efficiency of ADP phosphorylation, particularly after the addition of Ca<sup>2+</sup>. The presence of the cytosolic fraction mitigated mitochondrial depolarization but made it sustained. Carboxyatractyloside diminished the PIO-dependent depolarization. PIO activated proton transport in deenergized mitochondria but not in artificial phospholipid vesicles. PIO had no effect on K<sup>+</sup> and Ca<sup>2+</sup> inward transport but drastically decreased the mitochondrial Ca<sup>2+</sup>-retention capacity and protective effects of adenine nucleotides against mPTP opening. Thus, PIO is a mild, partly ATP/ADP-translocase-dependent, uncoupler and a modulator of ATP production and mPTP sensitivity to Ca<sup>2+</sup> and adenine nucleotides. These properties contribute to both therapeutic and adverse effects of PIO. |
| first_indexed | 2024-03-10T06:16:54Z |
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| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T06:16:54Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-132070f6221b47b3a2a2edfb90a56b862023-11-22T19:36:38ZengMDPI AGPharmaceuticals1424-82472021-10-011410104510.3390/ph14101045Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability TransitionEkaterina S. Kharechkina0Anna B. Nikiforova1Konstantin N. Belosludtsev2Tatyana I. Rokitskaya3Yuri N. Antonenko4Alexey G. Kruglov5Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, RussiaInstitute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, RussiaInstitute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, RussiaBelozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, RussiaBelozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, RussiaInstitute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, RussiaPioglitazone (PIO) is an insulin-sensitizing antidiabetic drug, which normalizes glucose and lipid metabolism but may provoke heart and liver failure and chronic kidney diseases. Both therapeutic and adverse effects of PIO can be accomplished through mitochondrial targets. Here, we explored the capability of PIO to modulate the mitochondrial membrane potential (ΔΨ<sub>m</sub>) and the permeability transition pore (mPTP) opening in different models in vitro. ΔΨ<sub>m</sub> was measured using tetraphenylphosphonium and the fluorescent dye rhodamine 123. The coupling of oxidative phosphorylation was estimated polarographically. The transport of ions and solutes across membranes was registered by potentiometric and spectral techniques. We found that PIO decreased ΔΨ<sub>m</sub> in isolated mitochondria and intact thymocytes and the efficiency of ADP phosphorylation, particularly after the addition of Ca<sup>2+</sup>. The presence of the cytosolic fraction mitigated mitochondrial depolarization but made it sustained. Carboxyatractyloside diminished the PIO-dependent depolarization. PIO activated proton transport in deenergized mitochondria but not in artificial phospholipid vesicles. PIO had no effect on K<sup>+</sup> and Ca<sup>2+</sup> inward transport but drastically decreased the mitochondrial Ca<sup>2+</sup>-retention capacity and protective effects of adenine nucleotides against mPTP opening. Thus, PIO is a mild, partly ATP/ADP-translocase-dependent, uncoupler and a modulator of ATP production and mPTP sensitivity to Ca<sup>2+</sup> and adenine nucleotides. These properties contribute to both therapeutic and adverse effects of PIO.https://www.mdpi.com/1424-8247/14/10/1045permeability transition poreunilamellar vesiclesadenine nucleotide translocaseuncoupling proteinATP production |
| spellingShingle | Ekaterina S. Kharechkina Anna B. Nikiforova Konstantin N. Belosludtsev Tatyana I. Rokitskaya Yuri N. Antonenko Alexey G. Kruglov Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition Pharmaceuticals permeability transition pore unilamellar vesicles adenine nucleotide translocase uncoupling protein ATP production |
| title | Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition |
| title_full | Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition |
| title_fullStr | Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition |
| title_full_unstemmed | Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition |
| title_short | Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition |
| title_sort | pioglitazone is a mild carrier dependent uncoupler of oxidative phosphorylation and a modulator of mitochondrial permeability transition |
| topic | permeability transition pore unilamellar vesicles adenine nucleotide translocase uncoupling protein ATP production |
| url | https://www.mdpi.com/1424-8247/14/10/1045 |
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