Abstract
Peroxisomes are versatile single membrane-enclosed cytoplasmic organelles, involved in reactive oxygen species (ROS) and lipid metabolism and diverse other metabolic processes. Peroxisomal disorders result from mutations in Pex genes-encoded proteins named peroxins (PEX proteins) and single peroxisomal enzyme deficiencies. The PEX11 protein family (α, β, and γ isoforms) plays an important role in peroxisomal proliferation and fission. However, their specific functions and the metabolic impact caused by their deficiencies have not been precisely characterized. To understand the systemic molecular alterations caused by peroxisomal defects, here we utilized untreated peroxisomal biogenesis factor 11α knockout (Pex11α KO) mouse model and performed serial relative-quantitative lipidomic, metabolomic, and proteomic analyses of serum, liver, and heart tissue homogenates. We demonstrated significant specific changes in the abundances of multiple lipid species, polar metabolites, and proteins and dysregulated metabolic pathways in distinct biological specimens of the Pex11α KO adult mice in comparison to the wild type (WT) controls. Overall, the present study reports comprehensive semi-quantitative molecular omics information of the Pex11α KO mice, which might serve in the future as a reference for a better understanding of the roles of Pex11α and underlying pathophysiological mechanisms of peroxisomal biogenesis disorders.Graphical abstract
Highlights
Peroxisomes are small (0.1–0.5 μm in diameter), single membrane bound, subcellular organelles present in almost every eukaryotic cell
In order to characterize the metabolic alterations occurring due to Pex11alpha deficiency, we investigated changes in the lipidome, metabolome, and proteome of different biological specimens from Pex11α KO adult mice using a liquid–liquid extraction method combined with untargeted sequential omics approaches by ultra-highperformance liquid chromatography equipped with highresolution tandem mass spectrometry (UHPLC-HRMS/MS)
Our study provides extensive semi-quantitative molecular information on the metabolic alterations in Pex11α KO mice, which will complement the understanding of the molecular functions of Pex11α and underlying pathophysiological mechanisms of peroxisomal biogenesis disorders
Summary
Peroxisomes are small (0.1–0.5 μm in diameter), single membrane bound, subcellular organelles present in almost every eukaryotic cell. The functional importance of peroxisomal metabolism for health in humans is emphasized by the existence of numerous peroxisomal disorders These devastating genetic human diseases are either resulting from mutations in Pex genes (peroxisomal biogenesis disorders, PBDs, or Zellweger spectrum disorders, ZSDs) or genes encoding single peroxisomal enzymes (peroxisomal enzyme deficiencies, PEDs) [1]. In both cases, the specific metabolic functions of multiple organs (such as brain, liver, kidney, adrenal gland, testis, bone, and many others) are severely disturbed, affecting the organism at a systemic level and often resulting in premature death. The processes that are usually affected are the fatty acid β- and α-oxidation, the plasmalogens biosynthesis, the glyoxylate metabolism, the bile acid synthesis, and the H 2O2 metabolism [7, 8]
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