Msp1/ATAD1 restores mitochondrial function in Zellweger Spectrum Disease

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.

Current advances in the function and biogenesis of peroxisomes and their roles in health and disease

“…Remarkably, mitochondrial function in PEX3 and PEX16 deficient fibroblasts derived from human patients with PBD could be rescued by overexpressing ATAD1, an AAA-ATPase that functions in mitochondrial quality control. Although it is still unclear whether mitochondrial defects directly contribute to PBD pathophysiology or are a secondary result of nonfunctioning peroxisomes, protecting mitochondrial function by supporting quality control pathways seems to be a promising target for an alternative therapy of peroxisomal disorders (Nuebel et al 2020).…”