Peroxisomes Are Required for Lipid Metabolism and Muscle Function in Drosophila melanogaster

Abstract

Peroxisomes are ubiquitous organelles that perform lipid and reactive oxygen species metabolism. Defects in peroxisome biogenesis cause peroxisome biogenesis disorders (PBDs). The most severe PBD, Zellweger syndrome, is characterized in part by neuronal dysfunction, craniofacial malformations, and low muscle tone (hypotonia). These devastating diseases lack effective therapies and the development of animal models may reveal new drug targets. We have generated Drosophila mutants with impaired peroxisome biogenesis by disrupting the early peroxin gene pex3, which participates in budding of pre-peroxisomes from the ER and peroxisomal membrane protein localization. pex3 deletion mutants lack detectible peroxisomes and die before or during pupariation. At earlier stages of development, larvae lacking Pex3 display reduced size and impaired lipid metabolism. Selective loss of peroxisomes in muscles impairs muscle function and results in flightless animals. Although, hypotonia in PBD patients is thought to be a secondary effect of neuronal dysfunction, our results suggest that peroxisome loss directly affects muscle physiology, possibly by disrupting energy metabolism. Understanding the role of peroxisomes in Drosophila physiology, specifically in muscle cells may reveal novel aspects of PBD etiology.

Acsl, the Drosophila ortholog of intellectual-disability-related ACSL4, inhibits synaptic growth by altered lipids

“…1Q-Q″), suggesting a role for these proteins in the activation of VLCFAs for peroxisomal degradation. Indeed, in animal models and patients with impaired peroxisomal function, accumulation of VLCFAs or increased levels of lipid species with longer fatty acid chains is observed (Chen et al, 2010;Faust et al, 2014;Wanders and Waterham, 2006). Thus, a defect in peroxisomal VLCFA degradation might underlie the elevation in sphingolipid species with VLCFA chains in Acsl mutant brains (Fig.…”

Distinct Roles for Peroxisomal Targeting Signal Receptors Pex5 and Pex7 in Drosophila

“…Mutation of Drosophila Pex genes is linked to a range of phenotypes, including lethality (Pex1, Pex3, Pex19) and male sterility (Pex16) (Beard and Holtzman 1987;Chen et al 2010;Mast et al 2011;Nakayama et al 2011;Faust et al 2014;Bülow et al 2018). In Drosophila Schneider 2 (S2) cells, knockdown of the Pex5 transcript reduces targeting of PTS1-containing proteins to peroxisomes, while depletion or overexpression of the Pex7 transcript leads to smaller or larger peroxisomes, respectively, than normal (Baron et al 2016).…”

A Systematic Cell‐Based Analysis of Localization of Predicted Drosophila Peroxisomal Proteins

“…The fruit fly Drosophila is a well validated, readily tractable organism to model many human disorders , including the PBDs . However, while previous studies have established a few specific homologues of Pex and other peroxisomal enzyme genes, in general the overall functional conservation of these pathways in Drosophila has not been tested. Previous in silico comparison of the human and Drosophila genome sequences identified a group of 82 potential Drosophila homologues of human peroxisome‐associated genes from a query encompassing 112 human peroxisomal protein sequences .…”