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Cited by 210Metabolism and Genetic DisordersMitochondrial Function and PathologyAutophagy in Disease and Therapy

Mitochondrial Alterations Caused by Defective Peroxisomal Biogenesis in a Mouse Model for Zellweger Syndrome (PEX5 Knockout Mouse)

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Baumgart, Eveline, Vanhorebeek, Ilse, Grabenbauer, Markus, Borgers, Marcel, Declercq, Peter E., Fahimi, H. Dariush, Baes, Myriam·2001·The American Journal of Pathology
DOI 10.1016/s0002-9440(10)62534-5PMC PMC1850512
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Abstract

Zellweger syndrome (cerebro-hepato-renal syndrome) is the most severe form of the peroxisomal biogenesis disorders leading to early death of the affected children. To study the pathogenetic mechanisms causing organ dysfunctions in Zellweger syndrome, we have recently developed a knockout-mouse model by disrupting the PEX5 gene, encoding the targeting receptor for most peroxisomal matrix proteins (M Baes, P Gressens, E Baumgart, P Carmeliet, M Casteels, M Fransen, P Evrard, D Fahimi, PE Declercq, D Collen, PP van Veldhoven, GP Mannaerts: A mouse model for Zellweger syndrome. Nat Genet 1997, 17:49-57). In this study, we present evidence that the absence of functional peroxisomes, causing a general defect in peroxisomal metabolism, leads to proliferation of pleomorphic mitochondria with severe alterations of the mitochondrial ultrastructure, changes in the expression and activities of mitochondrial respiratory chain complexes, and an increase in the heterogeneity of the mitochondrial compartment in various organs and specific cell types (eg, liver, proximal tubules of the kidney, adrenal cortex, heart, skeletal and smooth muscle cells, neutrophils). The changes of mitochondrial respiratory chain enzymes are accompanied by a marked increase of mitochondrial manganese-superoxide dismutase, as revealed by in situ hybridization and immunocytochemistry, suggesting increased production of reactive oxygen species in altered mitochondria. This increased oxidative stress induced probably by defective peroxisomal antioxidant mechanisms combined with accumulation of lipid intermediates of peroxisomal beta-oxidation system could contribute significantly to the pathogenesis of multiple organ dysfunctions in Zellweger syndrome.

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  1. [11]11. Hajra AK, Das AK: Lipid biosynthesis in peroxisomes. Ann NY Acad Sci 1996, 804:129 -141
  2. [16]16. Edited by CR Scriver, AL Beaudet, WS Sly, D Valle. New York, McGraw-Hill, 1995, pp 2287-2349
  3. [19]19. Gressens P, Baes M, Leroux P, Lombet A, Van Veldhoven P, Janssen A, Vamecq J, Marret S, Evrard P: Neuronal migration disorder in Zellweger mice is secondary to glutamate receptor dysfunction. Ann Neurol 2000, 48:336 -343
  4. [28]28. Grabenbauer M, Fahimi HD, Baumgart E: Detection of peroxisomal proteins and their mRNAs in fetal and newborn mice. J Histochem Cytochem 2001, 49:155-164
  5. [32]32. Fahimi HD: Cytochemical localization of catalase in rat hepatic mi- crobodies (peroxisomes). J Cell Biol 1969, 43:275-288

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Authors
Baumgart, E., Vanhorebeek, I., Grabenbauer, M., Borgers, M., Declercq, P. E., Fahimi, H. D., & Baes, M.
Affiliations
  • KU Leuven (BE)
  • Heidelberg University (DE)
  • Janssen (Belgium) (BE)
Corresponding author
Fahimi, H. Dariush
ORCID
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2001-10
Volume
159
Issue
4
Pages
1477-1494
ISSN
0002-9440 (ISSN-L)
DOI
10.1016/s0002-9440(10)62534-5
PMC
PMC1850512
OpenAlex
W2151833520
Cited by
210
References
95
Citations by year
2026: 4 · 2025: 11 · 2024: 10 · 2023: 5 · 2022: 11 · 2021: 8 · 2020: 10 · 2019: 12 · 2018: 11 · 2017: 6 · 2016: 11 · 2015: 8 · 2014: 10 · 2013: 10 · 2012: 8
FWCI
3.28
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
Deutsche Forschungsgemeinschaft (Ba 1155/1-4, SFB 601-B1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
Zellweger syndrome, peroxisome biogenesis disorders, mitochondrial ultrastructure, respiratory chain complexes, manganese superoxide dismutase, reactive oxygen species, oxidative stress, peroxisomal beta-oxidation, lipid intermediates, organ dysfunction
MeSH terms
Peroxisome-Targeting Signal 1 Receptor, Adenosine Triphosphate, Animals, Autophagy, Blood Cells, Electron Transport Complex IV, Cytoplasm, Disease Models, Animal, Electron Transport, Mitochondria, Mitochondria, Heart, Mitochondria, Liver, NADH, NADPH Oxidoreductases, Oxidation-Reduction, Superoxide Dismutase, Tissue Distribution, Zellweger Syndrome, Reactive Oxygen Species, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Peroxisomes, Hepatocytes, Electron Transport Complex I, Mice

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