Related Experiment Video
Updated: Jul 27, 2026
Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess
Published on: June 1, 2022
Mitochondrial alterations caused by defective peroxisomal biogenesis in a mouse model for Zellweger syndrome (PEX5
E Baumgart1, I Vanhorebeek, M Grabenbauer
1Department of Anatomy and Cell Biology, Division of Medical Cell Biology, University of Heidelberg, Heidelberg, Germany.
Insights
Zellweger syndrome, a peroxisomal disorder, causes severe organ dysfunction and early death. This study reveals that defective peroxisomes lead to mitochondrial damage and oxidative stress, contributing to disease pathology.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- Zellweger syndrome is the most severe form of peroxisomal biogenesis disorders.
- It leads to early mortality in affected children.
- Understanding its pathogenetic mechanisms is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the pathogenetic mechanisms underlying organ dysfunctions in Zellweger syndrome.
- To analyze the impact of peroxisomal dysfunction on mitochondrial morphology and function.
- To explore the role of oxidative stress in Zellweger syndrome pathogenesis.
Main Methods:
- Development of a PEX5 knockout-mouse model for Zellweger syndrome.
- Analysis of mitochondrial ultrastructure and heterogeneity in various organs.
- Assessment of mitochondrial respiratory chain complex expression and activity.
- In situ hybridization and immunocytochemistry to evaluate manganese-superoxide dismutase levels.
Main Results:
- Absence of functional peroxisomes leads to pleomorphic mitochondria with altered ultrastructure.
- Significant changes in mitochondrial respiratory chain complexes and increased heterogeneity were observed.
- Elevated manganese-superoxide dismutase suggests increased reactive oxygen species production.
- Oxidative stress and accumulation of lipid intermediates contribute to organ dysfunction.
Conclusions:
- Defective peroxisomal metabolism in Zellweger syndrome causes profound mitochondrial alterations.
- Increased oxidative stress, stemming from peroxisomal dysfunction, plays a significant role in disease pathogenesis.
- Mitochondrial dysfunction and oxidative stress are key contributors to the multiple organ dysfunctions observed in Zellweger syndrome.
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.
Related Concept Videos
02:59Animal Mitochondrial Genetics
01:27Protein Import into the Peroxisomes
Peroxisomal Protein Import:
Peroxisomes lack the genetic machinery required to code for their own proteins. Hence, most peroxisomal membrane, lumenal and transmembrane proteins are synthesized in the cytoplasm or ER and transported to the peroxisome...