Deficiency of a Retinal Dystrophy Protein, Acyl-CoA Binding Domain-containing 5 (ACBD5), Impairs Peroxisomal β-Oxidation of Very-long-chain Fatty Acids

Abstract

Edited by Dennis R. VoelkerAcyl-CoA binding domain-containing 5 (ACBD5) is a peroxisomal protein that carries an acyl-CoA binding domain (ACBD) at its N-terminal region. The recent identification of a mutation in the ACBD5 gene in patients with a syndromic form of retinal dystrophy highlights the physiological importance of ACBD5 in humans. However, the underlying pathogenic mechanisms and the precise function of ACBD5 remain unclear. We herein report that ACBD5 is a peroxisomal tail-anchored membrane protein exposing its ACBD to the cytosol. Using patient-derived fibroblasts and ACBD5 knock-out HeLa cells generated via genome editing, we demonstrate that ACBD5 deficiency causes a moderate but significant defect in peroxisomal ␤-oxidation of very-long-chain fatty acids (VLCFAs) and elevates the level of cellular phospholipids containing VLCFAs without affecting peroxisome biogenesis, including the import of membrane and matrix proteins. Both the N-terminal ACBD and peroxisomal localization of ACBD5 are prerequisite for efficient VLCFA ␤-oxidation in peroxisomes. Furthermore, ACBD5 preferentially binds very-long-chain fatty acyl-CoAs (VLC-CoAs). Together, these results suggest a direct role of ACBD5 in peroxisomal VLCFA ␤-oxidation. Based on our findings, we propose that ACBD5 captures VLC-CoAs on the cytosolic side of the peroxisomal membrane so that the transport of VLC-CoAs into peroxisomes and subsequent ␤-oxidation thereof can proceed efficiently. Our study reclassifies ACBD5-related phenotype as a novel peroxisomal disorder.

Organelle interplay—peroxisome interactions in health and disease

“…The first patients diagnosed with a genetic ACBD5 deficiency were three siblings presenting with retinal dystrophy and white matter changes . Further characterization of those and another patient revealed a peroxisome‐based disorder with progressive leukodystrophy, ataxia, progressive microcephaly with facial dysmorphisms, in addition to retinal dystrophy . In all cases, ACBD5 protein was absent due to a homozygous splice site mutation or a deleterious homozygous mutation deleting exons 7 and 8, causing a premature stop codon .…”

Peroxisome biogenesis, membrane contact sites, and quality control

“…Conversely, overexpression of the tethers in WT cells (VAPB, ACBD4, and ACBD5) induces contact sites [157]. The ACBD domain is not essential for peroxisome-ER tethering, but it is most probably required for the lipid exchange, as mutation in this domain affects b-oxidation of very-long-chain fatty acids in peroxisomes [161]. In agreement with this function, the total cellular levels of plasmalogens and cholesterol were reduced in the absence of these tethers [65].…”

Artificial import substrates reveal an omnivorous peroxisomal importomer

“…Recent work indicates that the peroxisomes are tethered to the endoplasmic reticulum (ER) through direct interaction between the peroxisomal Acyl‐CoA Binding Domain Containing protein 5 (ACBD5) and the ER vesicle‐associated membrane protein‐associated protein B/C (VAPB) . Peroxisomes do not appear to be adversely affected by ACBD5 deletion . However, under certain conditions membrane expansion appears to be defective when ACBD5 is absent .…”

“…52,53 Peroxisomes do not appear to be adversely affected by ACBD5 deletion. 54 However, under certain conditions membrane expansion appears to be defective when ACBD5 is absent. 52,53 Interestingly, as with all the membrane proteins we examined, ACBD5 also accumulates during matrix import-induced membrane expansion ( Figure S4).…”