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

Zellweger syndrome (cerebro-hepato-renal syndrome) is the most severe form of the peroxisomal biogenesis disorders leading to early death of the affec ted children. To study the pathogenetic mechanisms causing organ dysfunctio ns in Zellweger syndrome, we have recently developed a knockout-mouse model by disrupting the PEX5 gene, encoding the targeting receptor for most pero xisomal matrix proteins (M Baes, P Gressens, E Baumgart, P Carmeliet, M Cas teels, M Fransen, P Evrard, D Fahimi, PE Declercq, D Collen, PP van Veldhov en, GP Mannaerts: A mouse model for Zellweger syndrome. Nat Genet 1997, 17: 49-57(1)). In this study, we present evidence that the absence of functiona l peroxisomes, causing a general defect in peroxisomal metabolism, leads to proliferation of pleomorphic mitochondria with severe alterations of the m itochondrial ultrastructure, changes in the expression and activities of mi tochondrial respiratory chain complexes, and an increase in the heterogenei ty of the mitochondrial compartment in various organs and specific cell typ es (eg, liver, proximal tubules of the kidney, adrenal cortex, heart, skele tal and smooth muscle cells, neutrophils). The changes of mitochondrial res piratory chain enzymes are accompanied by a marked increase of mitochondria l manganese-superoxide dismutase, as revealed by in situ hybridization and immunocytochemistry, suggesting increased production of reactive oxygen spe cies in altered mitochondria. This increased oxidative stress induced proba bly by defective peroxisomal antioxidant mechanisms combined with accumulat ion of lipid intermediates of peroxisomal beta -oxidation system could cont ribute significantly to the pathogenesis of multiple organ dysfunctions in Zellweger syndrome.