Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse

Michael F. Wangler, Yu Hsin Chao, Vafa Bayat, Nikolaos Giagtzoglou, Abhijit Babaji Shinde, Nagireddy Putluri, Cristian Coarfa, Taraka Donti, Brett H. Graham, Joseph E. Faust, James A. McNew, Ann Moser, Marco Sardiello, Myriam Baes, Hugo J. Bellen

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere1006825
JournalPLoS Genetics
Volume13
Issue number6
DOIs
StatePublished - 2017

Fingerprint

genes
Carbohydrate Metabolism
Biogenesis
Drosophila
Genes
carbohydrate
peroxisomes
carbohydrate metabolism
mutants
mice
Peroxisomes
Carbohydrates
defect
metabolism
gene
biochemical pathways
carbohydrates
biogenesis
Diptera
enzymes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Wangler, M. F., Chao, Y. H., Bayat, V., Giagtzoglou, N., Shinde, A. B., Putluri, N., ... Bellen, H. J. (2017). Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse. PLoS Genetics, 13(6), [e1006825]. DOI: 10.1371/journal.pgen.1006825

Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse. / Wangler, Michael F.; Chao, Yu Hsin; Bayat, Vafa; Giagtzoglou, Nikolaos; Shinde, Abhijit Babaji; Putluri, Nagireddy; Coarfa, Cristian; Donti, Taraka; Graham, Brett H.; Faust, Joseph E.; McNew, James A.; Moser, Ann; Sardiello, Marco; Baes, Myriam; Bellen, Hugo J.

In: PLoS Genetics, Vol. 13, No. 6, e1006825, 2017.

Research output: Contribution to journalArticle

Wangler, MF, Chao, YH, Bayat, V, Giagtzoglou, N, Shinde, AB, Putluri, N, Coarfa, C, Donti, T, Graham, BH, Faust, JE, McNew, JA, Moser, A, Sardiello, M, Baes, M & Bellen, HJ 2017, 'Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse' PLoS Genetics, vol 13, no. 6, e1006825. DOI: 10.1371/journal.pgen.1006825
Wangler MF, Chao YH, Bayat V, Giagtzoglou N, Shinde AB, Putluri N et al. Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse. PLoS Genetics. 2017;13(6). e1006825. Available from, DOI: 10.1371/journal.pgen.1006825

Wangler, Michael F.; Chao, Yu Hsin; Bayat, Vafa; Giagtzoglou, Nikolaos; Shinde, Abhijit Babaji; Putluri, Nagireddy; Coarfa, Cristian; Donti, Taraka; Graham, Brett H.; Faust, Joseph E.; McNew, James A.; Moser, Ann; Sardiello, Marco; Baes, Myriam; Bellen, Hugo J. / Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse.

In: PLoS Genetics, Vol. 13, No. 6, e1006825, 2017.

Research output: Contribution to journalArticle

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