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(American Journal of Pathology. 2001;159:1477-1494.)
© 2001 American Society for Investigative Pathology

Regular Articles

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

Eveline Baumgart^*, Ilse Vanhorebeek, Markus Grabenbauer^*, Marcel Borgers, Peter E. Declercq, H. Dariush Fahimi^* and Myriam Baes

From the Department of Anatomy and Cell Biology,^*
Division of Medical Cell Biology, University of Heidelberg, Heidelberg, Germany; the Laboratory of Clinical Chemistry,
Faculty of Pharmacy, Katholieke Universiteit Leuven, Leuven, Belgium; the Department of Life Sciences,
Janssen Research Foundation, Beerse, Belgium; and the Department of Molecular Cell Biology,
Maastricht University, Maastricht, The Netherlands

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, 17:49–57¹ ). 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 chainenzymes are accompanied by a marked increase ofmitochondrial manganese-superoxide dismutase, asrevealed 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 ß-oxidation system could contribute significantly to the pathogenesis of multiple organ dysfunctions in Zellweger syndrome.

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