ATFS-1 regulates peroxisome assembly genes and protects both mitochondria and peroxisomes during peroxin perturbations

Abstract

Peroxisome biogenesis disorders lead to a myriad of clinical manifestations, among which is the dysfunction of the mitochondria. Mitochondria dysfunction is typically sensed by the UPRmt, a broad protective transcriptional response governed by the transcription factor ATFS-1. Here, we investigated the role of the UPRmt during peroxisomal stress. We show that mutations or knockdown of peroxins, the genes required for peroxisome assembly, lead to mitochondria dysfunction and the induction of the UPRmt in C.elegans. The UPRmt induced the transcription of the mitochondrial outer membrane translocase mspn-1 (ATAD-1), that in turn alleviated mitochondrial stress most likely by extracting mislocalized proteins. Importantly, ATFS-1 regulated the transcription of peroxins and the peroxisomal transporter pmp-4. A prx-5 loss of function strain induced a retrograde response that resulted in the transcriptional induction of peroxins, peroxisomal transporters, chaperons and proteases. And was dependent on ATFS-1 and on the peroxisome proliferator activator receptor alpha, NHR-49. Knockout of atfs-1 during peroxisomal stress resulted in severe developmental delays, import defects to peroxisomes and the appearance of large peroxisomal structures. We propose that ATFS-1 regulates the biogenesis of peroxisomes and protects the organism by alleviating the stress of both peroxisomes and mitochondria during peroxisomal stress.