Title: Mitochondria in peroxisome-deficient hepatocytes exhibit impaired respiration, depleted DNA, and PGC-1α independent proliferation
Authors: Peeters, Annelies
Shinde, Abhijit Babaji
Dirkx, Ruud
Smet, Joél
De Bock, Katrien
Espeel, Marc
Vanhorebeek, Ilse
Vanlander, Arnaud
Van Coster, Rudy
Carmeliet, Peter
Fransen, Marc
Van Veldhoven, Paul P
Baes, Myriam # ×
Issue Date: Feb-2015
Publisher: Elsevier
Series Title: Biochimica et Biophysica Acta. Molecular Cell Research vol:1853 issue:2 pages:285-98
Article number: S0167-4889(14)00415-7
Abstract: The tight interrelationship between peroxisomes and mitochondria is illustrated by their cooperation in lipid metabolism, antiviral innate immunity and shared use of proteins executing organellar fission. In addition, we previously reported that disruption of peroxisome biogenesis in hepatocytes severely impacts on mitochondrial integrity, primarily damaging the inner membrane. Here we investigated the molecular impairments of the dysfunctional mitochondria in hepatocyte selective Pex5 knockout mice. First, by using blue native electrophoresis and in-gel activity stainings we showed that the respiratory complexes were differentially affected with reduction of complexes I and III and incomplete assembly of complex V, whereas complexes II and IV were normally active. This resulted in impaired oxygen consumption in cultured Pex5(-/-) hepatocytes. Second, mitochondrial DNA was depleted causing an imbalance in the expression of mitochondrial- and nuclear-encoded subunits of the respiratory chain complexes. Third, mitochondrial membranes showed increased permeability and fluidity despite reduced content of the polyunsaturated fatty acid docosahexaenoic acid. Fourth, the affected mitochondria in peroxisome deficient hepatocytes displayed increased oxidative stress. Acute deletion of PEX5 in vivo using adeno-Cre virus phenocopied these effects, indicating that mitochondrial perturbations closely follow the loss of functional peroxisomes in time. Likely to compensate for the functional impairments, the volume of the mitochondrial compartment was increased several folds. This was not driven by PGC-1α but mediated by activation of PPARα, possibly through c-myc overexpression. In conclusion, loss of peroxisomal metabolism in hepatocytes perturbs the mitochondrial inner membrane, depletes mitochondrial DNA and causes mitochondrial biogenesis independent of PGC-1α.
ISSN: 0167-4889
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Cell Metabolism
Centre of Microbial and Plant Genetics
Exercise Physiology Research Group
Laboratory of Intensive Care Medicine
Laboratory of Angiogenesis and Vascular Metabolism (VIB-KU Leuven Centre for Cancer Biology) (+)
Laboratory of Lipid Biochemistry and Protein Interactions
× corresponding author
# (joint) last author

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