Abstract
Peroxisome biogenesis disorders (PBD) are a group of multi-system human diseases due to mutations in the PEX genes that are responsible for peroxisome assembly and function. These disorders lead to global defects in peroxisomal function and result in severe brain, liver, bone and kidney disease. In order to study their pathogenesis we undertook a systematic genetic and biochemical study of Drosophila pex16 and pex2 mutants. These mutants are short-lived with defects in locomotion and activity. Moreover these mutants exhibit severe morphologic and functional peroxisomal defects. Using metabolomics we uncovered defects in multiple biochemical pathways including defects outside the canonical specialized lipid pathways performed by peroxisomal enzymes. These included unanticipated changes in metabolites in glycolysis, glycogen metabolism, and the pentose phosphate pathway, carbohydrate metabolic pathways that do not utilize known peroxisomal enzymes. In addition, mutant flies are starvation sensitive and are very sensitive to glucose deprivation exhibiting dramatic shortening of lifespan and hyperactivity on low-sugar food. We use bioinformatic transcriptional profiling to examine gene co-regulation between peroxisomal genes and other metabolic pathways and we observe that the expression of peroxisomal and carbohydrate pathway genes in flies and mouse are tightly correlated. Indeed key steps in carbohydrate metabolism were found to be strongly co-regulated with peroxisomal genes in flies and mice. Moreover mice lacking peroxisomes exhibit defective carbohydrate metabolism at the same key steps in carbohydrate breakdown. Our data indicate an unexpected link between these two metabolic processes and suggest metabolism of carbohydrates could be a new therapeutic target for patients with PBD.
Highlights
IntroductionPeroxisomes perform specific biochemical functions in the cell including fatty acid β-oxidation of very-longchain fatty acids (VLCFA) [4], α-oxidation of branched chain fatty acids [5, 6], plasmalogen biosynthesis [7, 8], and participate in the metabolism of reactive oxygen species [9] and glyoxylate [10, 11]
Peroxisomes are ubiquitous organelles present in all eukaryotic cells [1,2,3]
Our work suggests carbohydrate metabolism may be a crucial process to study in patients with Peroxisome biogenesis disorders (PBD)
Summary
Peroxisomes perform specific biochemical functions in the cell including fatty acid β-oxidation of very-longchain fatty acids (VLCFA) [4], α-oxidation of branched chain fatty acids [5, 6], plasmalogen biosynthesis [7, 8], and participate in the metabolism of reactive oxygen species [9] and glyoxylate [10, 11]. Human diseases due to autosomal recessive loss of function mutations in the PEX genes comprise a group of severe disorders known as peroxisome biogenesis disorders (PBD) with involvement of brain, bone, kidney and liver and death within the first year of life [1, 2, 16, 17]. A more general alteration of peroxisomal lipids have been proposed as a developmental insult to the brain in PBD [22]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
