Polyhydroxybutyrate Targets Mammalian Mitochondria and Increases Permeability of Plasmalemmal and Mitochondrial Membranes

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From: PLoS ONE(Vol. 8, Issue 9)
Publisher: Public Library of Science
Document Type: Article
Length: 7,561 words
Lexile Measure: 1430L

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Author(s): Pia A. Elustondo 1, Plamena R. Angelova 3, Michal Kawalec 2, Michal Michalak 2, Piotr Kurcok 2, Andrey Y. Abramov 3, Evgeny V. Pavlov 1,*

Introduction

Poly-3-hydroxybutyrate (PHB) is a polyhydroxyalkanoate, a polymer that belongs to the polyester class and consists of 3-hydroxybutyrate (HB) units. PHB is ubiquitously present in all living organisms ranging from bacteria to humans. Previous studies have identified two major pools of PHB. The first pool is a long chain or storage PHB, composed of up to 100,000 HB units. This polymer is found predominantly in certain types of bacteria and in these organisms it accumulates in PHB granules under conditions of nutrient limitation, playing a role in carbon and energy storage [1]. The second pool of PHB is a short chain or "complexed" PHB (cPHB), represented by polymers with chain lengths ranging from 2 to 100 monomeric units. The term "complexed" reflects the fact that this type of PHB is normally associated with other biological polymers including proteins and polyphosphates, whereas long chain PHB is normally organized in PHB granules. Unlike long chain storage PHB, cPHB has been found in all living organisms, suggesting it may have an important biological role [2]. Currently the biological functions of cPHB are not well understood and most likely, vary depending on the specific organism and the sub-cellular localization of the polymer. It has been demonstrated that cPHB is likely involved in the regulation of membrane transport. It has been shown that cPHB is directly involved in the formation of bacterial cation selective channels through the formation of a polyphosphate (polyP)/Ca2+ /PHB complex [3]. Furthermore, recent studies indicate that cPHB is closely associated with the protein part of the bacterial channels KcsA [4] and OmpA [5] and mammalian TRPM8 [6], [7] suggesting a role in controlling the function of these protein channels. Recent studies also suggest that endogenous PHB might play an important role in mitochondrial calcium transport [8]. However, the exact role of PHB in the physiological function of the cell remains poorly understood.

Previous experiments using artificial lipid membranes demonstrated that PHB can induce ion permeability [9], [10]. We hypothesized that this property of PHB can significantly affect ion transporting properties of biological membranes and consequently modify cell function. Herein, we performed experiments in which we studied the effect of synthetic cPHB polymer on the function of live cells and isolated mitochondria. In order to do this we used synthetic fluorophore-labeled cPHB (fluo-PHB). We found that when added to live cells fluo-PHB redistributes into the mitochondria and activates their cation transport. We conclude that in mitochondrial membranes PHB acts as a potent ionophore. Due to the lack of information about the levels of endogenous mitochondrial, PHB effects seen in our study should be considered pharmacological rather than physiological. However, we propose the possibility that endogenous PHB might play a critical role in mitochondrial ion transport.

Results

Fluo-PHB Localizes to Mitochondria in Intact Live Cells

Taking into account that in eukaryotic cells native PHB is found...

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Gale Document Number: GALE|A478132745