Abstract
Peroxisomal Biogenesis Disorders (PBDs) are a class of inherited metabolic disorders with profound neurological and other phenotypes. The most severe PBDs are caused by mutations in peroxin genes, which result in nonfunctional peroxisomes typically through impaired protein import. In order to better understand the molecular causes of Zellweger Spectrum Disease (ZSD) -the most severe PBDs -, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that loss of peroxisomal import has no effect on peroxin mRNA expression or translational efficiency. Instead, peroxin proteins—still produced at high levels— aberrantly accumulate on the mitochondrial membrane, impairing respiration and ATP generation. Finally, we rescued mitochondrial function in fibroblasts derived from human patients with ZSD by overexpressing ATAD1, an AAA-ATPase that functions in mitochondrial quality control. These findings might provide a new focus of PBD therapies in supporting quality control pathways that protect mitochondrial function.
Competing Interest Statement
The University of Utah has filed a patent related to ATAD1, of which E.N., Y.C.C, and J.R. are listed as co-inventors. Next to NIH funding grant money was received from the Global Foundation for Peroxisomal Disorders in collaboration with the Wynne Mateffy Research Foundation. All other authors declare no competing interests.
Abbreviations
- PBDs
- Peroxisomal Biogenesis Disorders
- ZSD
- Zellweger Spectrum Disease
- ATP
- Adenosine-tri-phosphate
- RNA-Seq
- RNA-Sequencing
- TE
- translational efficiency
- GET
- gated entry of tail anchored proteins
- SDS
- sodium-dodecyl-sulfate
- BN
- blue native
- PAGE
- polyacryl-gel-electrophoresis
- EM
- electron microscopy
- ER
- endoplasmatic reticulum
- PerMit
- peroxisomal and mitochondrial tether