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

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.
PMID
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Authors

Mayor MeshTerms

Carbohydrate Metabolism

Keywords
Journal Title plos genetics
Publication Year Start




PMID- 28640802
OWN - NLM
STAT- MEDLINE
DA  - 20170622
DCOM- 20170706
LR  - 20170706
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Linking)
VI  - 13
IP  - 6
DP  - 2017 Jun
TI  - Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate
      metabolism in Drosophila and mouse.
PG  - e1006825
LID - 10.1371/journal.pgen.1006825 [doi]
AB  - 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.
FAU - Wangler, Michael F
AU  - Wangler MF
AUID- ORCID: http://orcid.org/0000-0001-5245-5910
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine (BCM),
      Houston, TX, United States of America.
AD  - Texas Children's Hospital, Houston TX, United States of America.
AD  - Program in Developmental Biology, BCM, Houston, TX, United States of America.
AD  - Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital
      (TCH), Houston, TX, United States of America.
FAU - Chao, Yu-Hsin
AU  - Chao YH
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine (BCM),
      Houston, TX, United States of America.
FAU - Bayat, Vafa
AU  - Bayat V
AUID- ORCID: http://orcid.org/0000-0002-1524-0520
AD  - Program in Developmental Biology, BCM, Houston, TX, United States of America.
FAU - Giagtzoglou, Nikolaos
AU  - Giagtzoglou N
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine (BCM),
      Houston, TX, United States of America.
FAU - Shinde, Abhijit Babaji
AU  - Shinde AB
AUID- ORCID: http://orcid.org/0000-0002-2558-0916
AD  - KU Leuven, Laboratory of Cell Metabolism, Department of Pharmaceutical and
      Pharmacological Sciences, Leuven, Belgium.
FAU - Putluri, Nagireddy
AU  - Putluri N
AD  - Department of Molecular and Cellular Biology, BCM, Houston, TX, United States of 
      America.
FAU - Coarfa, Cristian
AU  - Coarfa C
AD  - Department of Molecular and Cellular Biology, BCM, Houston, TX, United States of 
      America.
FAU - Donti, Taraka
AU  - Donti T
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine (BCM),
      Houston, TX, United States of America.
FAU - Graham, Brett H
AU  - Graham BH
AUID- ORCID: http://orcid.org/0000-0001-8451-8154
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine (BCM),
      Houston, TX, United States of America.
FAU - Faust, Joseph E
AU  - Faust JE
AD  - Department of BioSciences, Rice University, Houston TX, United States of America.
FAU - McNew, James A
AU  - McNew JA
AD  - Department of BioSciences, Rice University, Houston TX, United States of America.
FAU - Moser, Ann
AU  - Moser A
AUID- ORCID: http://orcid.org/0000-0002-9147-1902
AD  - Kennedy Krieger Institute, Baltimore MD, United States of America.
FAU - Sardiello, Marco
AU  - Sardiello M
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine (BCM),
      Houston, TX, United States of America.
AD  - Program in Developmental Biology, BCM, Houston, TX, United States of America.
AD  - Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital
      (TCH), Houston, TX, United States of America.
FAU - Baes, Myriam
AU  - Baes M
AD  - KU Leuven, Laboratory of Cell Metabolism, Department of Pharmaceutical and
      Pharmacological Sciences, Leuven, Belgium.
FAU - Bellen, Hugo J
AU  - Bellen HJ
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine (BCM),
      Houston, TX, United States of America.
AD  - Texas Children's Hospital, Houston TX, United States of America.
AD  - Program in Developmental Biology, BCM, Houston, TX, United States of America.
AD  - Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital
      (TCH), Houston, TX, United States of America.
AD  - Howard Hughes Medical Institute, Houston, TX, United States of America.
AD  - Department of Neuroscience, BCM, Houston, TX, United States of America.
LA  - eng
GR  - K08 NS076547/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20170622
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
RN  - 0 (Drosophila Proteins)
RN  - 0 (Membrane Proteins)
RN  - 135847-86-8 (peroxisome assembly factor-1)
RN  - IY9XDZ35W2 (Glucose)
RN  - Peroxisome biogenesis disorders
SB  - IM
MH  - Animals
MH  - *Carbohydrate Metabolism
MH  - Drosophila/genetics/metabolism
MH  - Drosophila Proteins/genetics/metabolism
MH  - Glucose/metabolism
MH  - Membrane Proteins/genetics/metabolism
MH  - Mice
MH  - Mutation
MH  - Peroxisomal Disorders/*genetics
MH  - Peroxisomes/genetics/*metabolism
MH  - Transcriptome
EDAT- 2017/06/24 06:00
MHDA- 2017/07/07 06:00
CRDT- 2017/06/23 06:00
PHST- 2017/01/09 [received]
PHST- 2017/05/16 [accepted]
AID - 10.1371/journal.pgen.1006825 [doi]
AID - PGENETICS-D-17-00036 [pii]
PST - epublish
SO  - PLoS Genet. 2017 Jun 22;13(6):e1006825. doi: 10.1371/journal.pgen.1006825.
      eCollection 2017 Jun.