Mitochondrial alterations caused by defective peroxisomal biogenesis in a mouse model for Zellweger syndrome (PEX5 knockout mouse)

Am J Pathol. 2001 Oct;159(4):1477-94. doi: 10.1016/S0002-9440(10)62534-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Autophagy / physiology
  • Blood Cells / ultrastructure
  • Cytoplasm / physiology
  • Disease Models, Animal
  • Electron Transport / physiology
  • Electron Transport Complex I
  • Electron Transport Complex IV / metabolism
  • Hepatocytes / metabolism
  • Mice
  • Mice, Knockout / genetics
  • Mitochondria / ultrastructure*
  • Mitochondria, Heart / metabolism
  • Mitochondria, Liver / metabolism
  • Mitochondria, Liver / ultrastructure
  • NADH, NADPH Oxidoreductases / antagonists & inhibitors
  • NADH, NADPH Oxidoreductases / metabolism
  • Oxidation-Reduction
  • Peroxisome-Targeting Signal 1 Receptor
  • Peroxisomes / metabolism*
  • Reactive Oxygen Species / metabolism
  • Receptors, Cytoplasmic and Nuclear / deficiency*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Superoxide Dismutase / metabolism
  • Tissue Distribution
  • Zellweger Syndrome / metabolism*
  • Zellweger Syndrome / pathology*


  • Peroxisome-Targeting Signal 1 Receptor
  • Pex5 protein, mouse
  • Reactive Oxygen Species
  • Receptors, Cytoplasmic and Nuclear
  • Adenosine Triphosphate
  • Superoxide Dismutase
  • NADH, NADPH Oxidoreductases
  • Electron Transport Complex IV
  • Electron Transport Complex I