Abstract
BackgroundPeroxisomal metabolic machinery requires a continuous flow of organic and inorganic solutes across peroxisomal membrane. Concerning small solutes, the molecular nature of their traffic has remained an enigma.Methods/Principal FindingsIn this study, we show that disruption in mice of the Pxmp2 gene encoding Pxmp2, which belongs to a family of integral membrane proteins with unknown function, leads to partial restriction of peroxisomal membrane permeability to solutes in vitro and in vivo. Multiple-channel recording of liver peroxisomal preparations reveals that the channel-forming components with a conductance of 1.3 nS in 1.0 M KCl were lost in Pxmp2 −/− mice. The channel-forming properties of Pxmp2 were confirmed with recombinant protein expressed in insect cells and with native Pxmp2 purified from mouse liver. The Pxmp2 channel, with an estimated diameter of 1.4 nm, shows weak cation selectivity and no voltage dependence. The long-lasting open states of the channel indicate its functional role as a protein forming a general diffusion pore in the membrane.Conclusions/SignificancePxmp2 is the first peroxisomal channel identified, and its existence leads to prediction that the mammalian peroxisomal membrane is permeable to small solutes while transfer of “bulky” metabolites, e.g., cofactors (NAD/H, NADP/H, and CoA) and ATP, requires specific transporters.
Highlights
Peroxisomes are small oxidative organelles found in all eukaryotes
In our study we tried to resolve two important interrelated problems in the physiology of mammalian peroxisomes: (i) the molecular foundation for the permeability of the peroxisomal membrane to solutes, and (ii) the functional role of Pxmp2, which belongs to a membrane protein family with a previously unknown function
Pxmp2 forms a channel in peroxisomal membrane According to our recent observation [6], the putative peroxisomal channels show single channel conductance of 1.3 nS and 2.5 nS in 1.0 M KCl, respectively, when crude peroxisomal membrane preparations from mouse liver were assayed in reconstitution experiments using lipid bilayers
Summary
Peroxisomes are small oxidative organelles found in all eukaryotes. They contain a matrix which is surrounded by a single membrane and consists mainly of soluble proteins. Peroxisomal enzymes are involved in a broad spectrum of metabolic pathways including conversion of lipids, amino- and hydroxyacids, purines and reactive oxygen species [1]. The carbon flow through peroxisomal pathways presupposes a continuous metabolite transfer across the peroxisomal membrane. The mechanism of this transfer represents a long-standing problem in the biology of peroxisomes. Peroxisomal metabolic machinery requires a continuous flow of organic and inorganic solutes across peroxisomal membrane. Concerning small solutes, the molecular nature of their traffic has remained an enigma
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