Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition.

Ekaterina S Kharechkina,Konstantin N Belosludtsev,Yuri N Antonenko,Anna B Nikiforova,Tatyana I Rokitskaya,Alexey G Kruglov

doi:10.3390/ph14101045

Abstract

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 (ΔΨm) and the permeability transition pore (mPTP) opening in different models in vitro. ΔΨm 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 ΔΨm 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.

Highlights

Introduction iationsPIO is a member of the thiazolidinedione class of insulin-sensitizing drugs, which are extensively used in the treatment of type 2 diabetes
We studied the effect of PIO on the pH value in large with unilamellar vesicles loaded with the probe Figure pyranine
We examined whether the effect of PIO on ∆Ψm in mitochondria is connected with the activation of proton or and with1 other reasons

Summary

Introduction

PIO is a member of the thiazolidinedione class of insulin-sensitizing drugs, which are extensively used in the treatment of type 2 diabetes. Its impact on diabetes is linked primarily to the binding and activation of the peroxisome proliferator-activated receptor-γ, which regulates the expression of numerous insulin-responsive genes involved in the control of glucose and lipid metabolism [1]. Due to its anti-inflammatory, antioxidant, and, perhaps, antibacterial and antifungal properties, PIO is considered as a promising medicine for the treatment of a range of pathologic states, including Alzheimer’s disease [5], depressive disorder [6], non-alcoholic fatty liver disease [7], renal ischemia-reperfusion injury [8], Licensee MDPI, Basel, Switzerland.

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