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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 (\u0394\u03a8m) and the permeability transition pore (mPTP) opening in different models in vitro. \u0394\u03a8m 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 \u0394\u03a8m in isolated mitochondria and intact thymocytes and the efficiency of ADP phosphorylation, particularly after the addition of Ca2+. 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+ and Ca2+ inward transport but drastically decreased the mitochondrial Ca2+-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 Ca2+ and adenine nucleotides. These properties contribute to both therapeutic and adverse effects of PIO.<\/jats:p>","DOI":"10.3390\/ph14101045","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T22:42:18Z","timestamp":1634251338000},"page":"1045","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition"],"prefix":"10.3390","volume":"14","author":[{"given":"Ekaterina S.","family":"Kharechkina","sequence":"first","affiliation":[{"name":"Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna B.","family":"Nikiforova","sequence":"additional","affiliation":[{"name":"Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5392-7035","authenticated-orcid":false,"given":"Konstantin N.","family":"Belosludtsev","sequence":"additional","affiliation":[{"name":"Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia"},{"name":"Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana I.","family":"Rokitskaya","sequence":"additional","affiliation":[{"name":"Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0244-855X","authenticated-orcid":false,"given":"Yuri N.","family":"Antonenko","sequence":"additional","affiliation":[{"name":"Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9215-7387","authenticated-orcid":false,"given":"Alexey G.","family":"Kruglov","sequence":"additional","affiliation":[{"name":"Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1210\/me.2013-1427","article-title":"Minireview: Challenges and opportunities in development of PPAR agonists","volume":"28","author":"Wright","year":"2014","journal-title":"Mol. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5389","DOI":"10.1038\/s41598-019-41854-2","article-title":"Efficacy and safety of pioglitazone monotherapy in type 2 diabetes mellitus: A systematic review and meta-analysis of randomised controlled trials","volume":"9","author":"Alam","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"102232","DOI":"10.1016\/j.dsx.2021.102232","article-title":"Meta-analysis of trials in non-alcoholic fatty liver disease with therapeutic interventions for metabolic syndrome","volume":"15","author":"Albert","year":"2021","journal-title":"Diabetes Metab. Syndr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"615409","DOI":"10.3389\/fendo.2021.615409","article-title":"Pioglitazone for NAFLD Patients With Prediabetes or Type 2 Diabetes Mellitus: A Meta-Analysis","volume":"12","author":"Lian","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S1474-4422(21)00043-0","article-title":"Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer\u2019s disease (TOMMORROW): A prognostic biomarker study and a phase 3, randomised, double-blind, placebo-controlled trial","volume":"20","author":"Burns","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"691200","DOI":"10.3389\/fphar.2021.691200","article-title":"Comparative Efficacy and Acceptability of Anti-inflammatory Agents on Major Depressive Disorder: A Network Meta-Analysis","volume":"12","author":"Hang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108984","DOI":"10.1016\/j.diabres.2021.108984","article-title":"Pioglitazone even at low dosage improves NAFLD in type 2 diabetes: Clinical and pathophysiological insights from a subgroup of the TOSCA. IT randomised trial","volume":"178","author":"Russo","year":"2021","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"707344","DOI":"10.3389\/fphys.2021.707344","article-title":"Pioglitazone Ameliorates Renal Ischemia-Reperfusion Injury via Inhibition of NF-\u03baB Activation and Inflammation in Rats","volume":"12","author":"Zou","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1186\/s12931-021-01823-8","article-title":"Post-treatment with the PPAR-\u03b3 agonist pioglitazone inhibits inflammation and bacterial growth during Klebsiella pneumonia","volume":"22","year":"2021","journal-title":"Respir Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1080\/07853890.2021.1916069","article-title":"Pioglitazone improves skeletal muscle functions in reserpine-induced fibromyalgia rat model","volume":"53","author":"Hassan","year":"2021","journal-title":"Ann. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"483","DOI":"10.4049\/jimmunol.2000565","article-title":"Pioglitazone Reverses Alcohol-Induced Alveolar Macrophage Phagocytic Dysfunction","volume":"207","author":"Yeligar","year":"2021","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"644095","DOI":"10.3389\/fcvm.2021.644095","article-title":"COVID-19 in Relation to Hyperglycemia and Diabetes Mellitus","volume":"8","author":"Alblihed","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"119706","DOI":"10.1016\/j.lfs.2021.119706","article-title":"Pioglitazone and\/or irbesartan ameliorate COPD-induced endothelial dysfunction in side stream cigarette smoke-exposed mice model","volume":"280","author":"Abdelhafez","year":"2021","journal-title":"Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"100745","DOI":"10.1016\/j.conctc.2021.100745","article-title":"Randomized, phase 1\/2, double-blind pioglitazone repositioning trial combined with antifungals for the treatment of cryptococcal meningitis\u2014PIO study","volume":"22","author":"Ribeiro","year":"2021","journal-title":"Contemp. Clin. Trials Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"113765","DOI":"10.1016\/j.expneurol.2021.113765","article-title":"Mild traumatic brain injury increases vulnerability to cerebral ischemia in mice","volume":"342","author":"Weil","year":"2021","journal-title":"Exp. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1056\/NEJMoa1010949","article-title":"Pioglitazone for diabetes prevention in impaired glucose tolerance","volume":"364","author":"DeFronzo","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/s12933-017-0617-4","article-title":"Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials","volume":"16","author":"Visseren","year":"2017","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1111\/apt.16575","article-title":"Review article: Non-alcoholic fatty liver disease and cardiovascular diseases: Associations and treatment considerations","volume":"54","author":"Polyzos","year":"2021","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"256","DOI":"10.2337\/diacare.27.1.256","article-title":"Thiazolidinedione use, fluid retention, and congestive heart failure: A consensus statement from the American Heart Association and American Diabetes Association","volume":"27","author":"Nesto","year":"2004","journal-title":"Diabetes Care"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lee, M.Y., Hsiao, P.J., Yang, Y.H., Lin, K.D., and Shin, S.J. (2014). The association of pioglitazone and urinary tract disease in type 2 diabetic Taiwanese: Bladder cancer and chronic kidney disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0085479"},{"key":"ref_21","unstructured":"McEvoy, G.K. (2017). AHFS Drug Information, American Society of Health-System Pharmacists. [59th ed.]."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s13340-018-0360-4","article-title":"Pioglitazone use and risk of bladder cancer: A systematic literature review and meta-analysis of observational studies","volume":"10","author":"Khanfir","year":"2019","journal-title":"Diabetol. Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1124\/mol.106.032458","article-title":"Glitazones induce astroglioma cell death by releasing reactive oxygen species from mitochondria: Modulation of cytotoxicity by nitric oxide","volume":"72","author":"Tranque","year":"2007","journal-title":"Mol. Pharmacol."},{"key":"ref_24","first-page":"27","article-title":"Mitochondrial dysfunction in diabetic cardiomyopathy: Effect of mesenchymal stem cell with PPAR-\u03b3 agonist or exendin-4. Exp","volume":"126","author":"Wassef","year":"2018","journal-title":"Clin. Endocrinol. Diabetes"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kiran, A.V.V.V.R., Kumari, G.K., and Krishnamurthy, P.T. (2021). Preliminary evaluation of anticancer efficacy of pioglitazone combined with celecoxib for the treatment of non-small cell lung cancer. Investig. New Drugs.","DOI":"10.1007\/s10637-021-01158-7"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s12032-021-01521-x","article-title":"Preliminary evaluation on the beneficial effects of pioglitazone in the treatment of endometrial cancer","volume":"38","author":"Kumari","year":"2021","journal-title":"Med. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/s12933-021-01294-7","article-title":"Rethinking pioglitazone as a cardioprotective agent: A new perspective on an overlooked drug","volume":"18","author":"Nesti","year":"2021","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s00395-016-0555-4","article-title":"Pioglitazone increases PGC1-\u03b1 signaling within chronically ischemic myocardium","volume":"111","author":"Butterick","year":"2016","journal-title":"Basic Res. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"658362","DOI":"10.3389\/fphar.2021.658362","article-title":"Pioglitazone Inhibits Diabetes-Induced Atrial Mitochondrial Oxidative Stress and Improves Mitochondrial Biogenesis, Dynamics, and Function Through the PPAR-\u03b3\/PGC-1\u03b1 Signaling Pathway","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s10557-008-6138-3","article-title":"Oral glyburide, but not glimepiride, blocks the infarct-size limiting effects of pioglitazone","volume":"22","author":"Lin","year":"2008","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1097\/01.fjc.0000188365.07635.57","article-title":"Pioglitazone mimics preconditioning in the isolated perfused rat heart: A role for the prosurvival kinases PI3K and P42\/44MAPK","volume":"46","author":"Wynne","year":"2005","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_32","first-page":"1158","article-title":"Myocardial protection by pioglita6zone, atorvastatin, and their combination: Mechanisms and possible interactions","volume":"291","author":"Ye","year":"2006","journal-title":"Am. J. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s10557-008-6115-x","article-title":"Antiapoptosis and mitochondrial effect of pioglitazone preconditioning in the ischemic\/reperfused heart of rat","volume":"22","author":"Li","year":"2008","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Jarrar, Y.B., Jarrar, Q., Abaalkhail, S.J., Kalloush, H.M., Naser, W., Zihlif, M., Shhab, M.A., Madani, A.E., Jamous, Y., and Lee, S.J. (2021). Molecular toxicological alterations in the mouse hearts induced by sub-chronic thiazolidinedione drugs administration. Fundam Clin Pharmacol.","DOI":"10.1111\/fcp.12694"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4174","DOI":"10.4161\/cc.22376","article-title":"Mitochondrial biogenesis in epithelial cancer cells promotes breast cancer tumor growth and confers autophagy resistance","volume":"11","author":"Salem","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_36","first-page":"825","article-title":"Study of the effects of ATP suppliers and thiol reductants on toxicity of pioglitazone in isolated rat liver mitochondria","volume":"14","author":"Jamshidzadeh","year":"2015","journal-title":"Iran. J. Pharm. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"92","DOI":"10.12793\/tcp.2021.29.e9","article-title":"Insulin sensitization causes accelerated sinus nodal dysfunction through autophagic dysregulation in hypertensive mice","volume":"29","author":"Woo","year":"2021","journal-title":"Transl. Clin. Pharmacol."},{"key":"ref_38","first-page":"252","article-title":"Identification of a novel mitochondrial protein (\u201cmitoNEET\u201d) cross-linked specifically by a thiazolidinedione photoprobe","volume":"286","author":"Colca","year":"2004","journal-title":"Am. J. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5616","DOI":"10.1021\/acs.biochem.8b00777","article-title":"The H2O2-resistant Fe-S redox switch mitoNEET acts as a pH sensor to repair stress-damaged Fe-S protein","volume":"57","author":"Mons","year":"2018","journal-title":"Biochemistry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1016\/j.bbamcr.2014.10.014","article-title":"Structure-function analysis of NEET proteins uncovers their role as key regulators of iron and ROS homeostasis in health and disease","volume":"1853","author":"Tamir","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/j.bbrc.2016.08.034","article-title":"CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation","volume":"478","author":"Yuan","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8277","DOI":"10.1073\/pnas.1706643114","article-title":"MitoNEET-dependent formation of intermitochondrial junctions","volume":"114","author":"Vernay","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5318","DOI":"10.1073\/pnas.0701078104","article-title":"MitoNEET is an iron-containing outer mitochondrial membrane protein that regulates oxidative capacity","volume":"104","author":"Wiley","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1073\/pnas.1715842115","article-title":"Structure of the human monomeric NEET protein MiNT and its role in regulating iron and reactive oxygen species in cancer cells","volume":"115","author":"Lipper","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"14676","DOI":"10.1073\/pnas.1313198110","article-title":"NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth","volume":"110","author":"Sohn","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.2337\/db15-1323","article-title":"MitoNEET-Parkin effects in pancreatic alpha- and beta-cells, cellular survival, and intrainsular cross talk","volume":"65","author":"Kusminski","year":"2016","journal-title":"Diabetes"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1038\/nm.2899","article-title":"MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity","volume":"18","author":"Kusminski","year":"2012","journal-title":"Nat. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3962","DOI":"10.1038\/ncomms4962","article-title":"MitoNEET-mediated effects on browning of white adipose tissue","volume":"5","author":"Kusminski","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"14342","DOI":"10.1073\/pnas.0707189104","article-title":"MitoNEET is a uniquely folded 2Fe 2S outer mitochondrial membrane protein stabilized by pioglitazone","volume":"104","author":"Raddock","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"13047","DOI":"10.1073\/pnas.1109986108","article-title":"Facile transfer of [2Fe-2S] clusters from the diabetes drug target mitoNEET to an apo-acceptor protein","volume":"108","author":"Zuris","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2606","DOI":"10.1038\/sj.onc.1210074","article-title":"GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization","volume":"26","author":"Tarze","year":"2007","journal-title":"Oncogene"},{"key":"ref_52","first-page":"75","article-title":"Paradoxical inhibition of glycolysis by pioglitazone opposes the mitochondriopathy caused by AIF deficiency","volume":"17","author":"Saunier","year":"2017","journal-title":"BioMedicine"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Ruiz, I., Sol\u00eds-Mu\u00f1oz, P., Fern\u00e1ndez-Moreira, D., Mu\u00f1oz-Yag\u00fce, T., and Sol\u00eds-Herruzo, J.A. (2013). Pioglitazone leads to an inactivation and disassembly of complex I of the mitochondrial respiratory chain. BMC Biol., 11.","DOI":"10.1186\/1741-7007-11-88"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1159\/000335804","article-title":"Acute mitochondrial actions of glitazones on the liver: A crucial parameter for their antidiabetic properties","volume":"28","author":"Sanz","year":"2011","journal-title":"Cell Physiol. Biochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.bmcl.2009.12.088","article-title":"Structure-based design of a thiazolidinedione which targets the mitochondrial protein mitoNEET","volume":"20","author":"Geldenhuys","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"115659","DOI":"10.1016\/j.taap.2021.115659","article-title":"Role of respiratory uncoupling in drug-induced mitochondrial permeability transition","volume":"15","author":"Sato","year":"2021","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1177\/0192623312441406","article-title":"The development of subcutaneous sarcomas in rodents exposed to peroxisome proliferators agonists: Hypothetical mechanisms of action and de-risking attitude","volume":"40","author":"Francone","year":"2012","journal-title":"Toxicol. Pathol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1111\/febs.13992","article-title":"Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes","volume":"284","author":"Shannon","year":"2017","journal-title":"FEBS J."},{"key":"ref_59","unstructured":"O\u2019Neil, M.J. (2013). The Merck Index\u2014An Encyclopedia of Chemicals, Drugs, and Biologicals, Royal Society of Chemistry. [15th ed.]."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1152\/physrev.1980.60.3.825","article-title":"Transport of protons across membranes by weak acids","volume":"60","author":"McLaughlin","year":"1980","journal-title":"Physiol. Rev."},{"key":"ref_61","first-page":"231","article-title":"Lithocholic acid induces two different calcium-dependent inner membrane permeability systems in liver mitochondria","volume":"11","author":"Dubinin","year":"2017","journal-title":"Biochemistry"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.bbagen.2019.01.003","article-title":"Regulation of permeability transition pore opening in mitochondria by external NAD(H)","volume":"1863","author":"Kharechkina","year":"2019","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_63","first-page":"274","article-title":"Permeability transition in rat liver mitochondria is modulated by the ATP-Mg\/Pi carrier","volume":"285","author":"Hagen","year":"2003","journal-title":"Am. J. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1111\/j.1432-1033.1989.tb14867.x","article-title":"The ATP\/ADP-antiporter is involved in the uncoupling effect of fatty acids on mitochondria","volume":"182","author":"Andreyev","year":"1989","journal-title":"Eur. J. Biochem."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"\u017duna, K., Jovanovi\u0107, O., Khailova, L.S., \u0160kulj, S., Brklja\u010da, Z., Kreiter, J., Kotova, E.A., Vazdar, M., Antonenko, Y.N., and Pohl, E.E. (2021). Mitochondrial Uncoupling Proteins (UCP1-UCP3) and Adenine Nucleotide Translocase (ANT1) Enhance the Protonophoric Action of 2,4-Dinitrophenol in Mitochondria and Planar Bilayer Membranes. Biomolecules, 11.","DOI":"10.3390\/biom11081178"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.cmet.2014.07.004","article-title":"Fatty acid flippase activity of UCP2 is essential for its proton transport in mitochondria","volume":"20","author":"Berardi","year":"2014","journal-title":"Cell Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1080\/10837450802498894","article-title":"Co-solvent solubilization of some poorly-soluble antidiabetic drugs","volume":"14","author":"Seedher","year":"2009","journal-title":"Pharm Dev. Technol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/s41580-018-0071-5","article-title":"Lipid transfer proteins: The lipid commute via shuttles, bridges and tubes","volume":"20","author":"Wong","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Geisler, J.G. (2019). 2,4 Dinitrophenol as Medicine. Cells, 8.","DOI":"10.3390\/cells8030280"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1385\/JMN:16:2-3:99","article-title":"Fatty acid transport: The diffusion mechanism in model and biological membranes","volume":"16","author":"Hamilton","year":"2001","journal-title":"J. Mol. Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/0014-5793(90)80480-7","article-title":"Inhibitors of the ATP\/ADP antiporter suppress stimulation of mitochondrial respiration and H+ permeability by palmitate and anionic detergents","volume":"272","author":"Brustovetsky","year":"1990","journal-title":"FEBS"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"27329","DOI":"10.1016\/S0021-9258(18)46989-X","article-title":"The reconstituted ADP\/ATP carrier can mediate H+ transport by free fatty acids, which is further stimulated by mersalyl","volume":"269","author":"Brustovetsky","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.biochi.2016.10.013","article-title":"UCP1: A transporter for H+ and fatty acid anions","volume":"134","author":"Bertholet","year":"2017","journal-title":"Biochimie"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/BF00762735","article-title":"Recent progress on regulation of the mitochondrial permeability transition pore; a cyclosporin-sensitive pore in the inner mitochondrial membrane","volume":"26","author":"Bernardi","year":"1994","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1038\/cdd.2011.139","article-title":"SCaMC-1 promotes cancer cell survival by desensitizing mitochondrial permeability transition via ATP\/ADP-mediated matrix Ca(2+) buffering","volume":"19","author":"Traba","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_76","first-page":"172","article-title":"Estimation of Pioglitazone Hydrochloride in Bulk Drug and Pharmaceutical Dosage Forms by Hydrotropy Technique and Oxidative-Coupling Reaction","volume":"6","author":"Ramakrishna","year":"2013","journal-title":"Asian J. Res. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Khailova, L.S., Firsov, A.M., Kotova, E.A., and Antonenko, Y.N. (2019). Interaction of Potent Mitochondrial Uncouplers with Thiol-Containing Antioxidants. Antioxidants, 8.","DOI":"10.3390\/antiox8060194"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1161\/ATVBAHA.112.300346","article-title":"Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors","volume":"33","author":"Saremi","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1111\/j.1474-9726.2008.00407.x","article-title":"Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity","volume":"7","author":"Cerqueira","year":"2008","journal-title":"Aging Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1126\/science.aaa0672","article-title":"Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats","volume":"347","author":"Perry","year":"2015","journal-title":"Science"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/0076-6879(67)10018-9","article-title":"Isolation of liver or kidney mitochondria","volume":"10","author":"Johnson","year":"1967","journal-title":"Methods Enzymol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.freeradbiomed.2014.06.005","article-title":"External mitochondrial NADH-dependent reductase of redox cyclers: VDAC1 or Cyb5R3?","volume":"74","author":"Nikiforova","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/S0021-9258(18)57021-6","article-title":"Determination of serum proteins by means of the biuret reaction","volume":"177","author":"Gornall","year":"1949","journal-title":"J. Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2490","DOI":"10.1016\/j.bpj.2008.12.3915","article-title":"A novel kinetic assay of mitochondrial ATP-ADP exchange rate mediated by the ANT","volume":"96","author":"Chinopoulos","year":"2009","journal-title":"Biophys. J."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.freeradbiomed.2021.03.036","article-title":"Mitochondria-targeted prooxidant effects of betulinic acid conjugated with delocalized lipophilic cation F16","volume":"168","author":"Dubinin","year":"2021","journal-title":"Free Radic Biol. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"18364","DOI":"10.1074\/jbc.274.26.18364","article-title":"A mechanism for tamoxifen-mediated inhibition of acidification","volume":"274","author":"Chen","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.bioelechem.2014.02.002","article-title":"Tuning the hydrophobicity overcomes unfavorable deprotonation making octylamino-substituted 7-nitrobenz-2-oxa-1,3-diazole (n-octylamino-NBD) a protonophore and uncoupler of oxidative phosphorylation in mitochondria","volume":"98","author":"Denisov","year":"2014","journal-title":"Bioelectrochemistry"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"5404","DOI":"10.1016\/S0021-9258(18)62769-3","article-title":"Ion transport by heart mitochondria. XX. Factors affecting passive osmotic swelling of isolated mitochondria","volume":"245","author":"Brierley","year":"1970","journal-title":"J. Biol. Chem."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/10\/1045\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:14:27Z","timestamp":1760166867000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/10\/1045"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,14]]},"references-count":88,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ph14101045"],"URL":"https:\/\/doi.org\/10.3390\/ph14101045","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,14]]}}}