Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
Hum Mol Genet. 2010 Feb 1;19(3):494-505. doi: 10.1093/hmg/ddp518. Epub 2009 Nov 17.
Peroxisomes are vital eukaryotic organelles that participate in lipid metabolism, in particular the metabolism of very-long-chain fatty acids (VLCFA). The biogenesis of peroxisomes is regulated by a set of peroxin proteins (PEX). In humans, mutations affecting peroxin protein production or function result in devastating diseases classified as peroxisome biogenesis disorders (PBD). The way in which peroxisomal dysfunction leads to the pathophysiological consequences of PBD is not well understood. Here we report that Drosophila pex mutants faithfully recapitulate several key features of human PBD, including impaired peroxisomal protein import, elevated VLCFA levels and growth retardation. Moreover, disruption of pex function results in spermatogenesis defects, including spermatocyte cytokinesis failure in Drosophila. Importantly, increased VLCFA levels enhance these spermatogenesis defects whereas reduced VLCFA levels alleviate them. Thus, regulation of proper VLCFA levels by pex genes is crucial for spermatogenesis. Together our study reveals an indispensable function of pex genes during spermatogenesis and provides a causative link between the phenotypic severity of pex mutants and VLCFA levels.
过氧化物酶体是真核生物中至关重要的细胞器，参与脂质代谢，特别是超长链脂肪酸 (VLCFA) 的代谢。过氧化物酶体的生物发生受一组过氧化物酶蛋白 (PEX) 调节。在人类中，影响过氧化物酶蛋白产生或功能的突变会导致破坏性疾病，这些疾病被归类为过氧化物酶体生物发生障碍 (PBD)。过氧化物酶体功能障碍导致 PBD 的病理生理后果的方式尚未得到很好的理解。在这里，我们报告果蝇 pex 突变体忠实地再现了人类 PBD 的几个关键特征，包括过氧化物酶体蛋白输入受损、VLCFA 水平升高和生长迟缓。此外，pex 功能的破坏导致精子发生缺陷，包括果蝇精母细胞胞质分裂失败。重要的是，增加 VLCFA 水平会加剧这些精子发生缺陷，而降低 VLCFA 水平则会减轻这些缺陷。因此，pex 基因对适当的 VLCFA 水平的调节对于精子发生至关重要。综上所述，我们的研究揭示了 pex 基因在精子发生过程中的不可或缺的功能，并为 pex 突变体的表型严重程度与 VLCFA 水平之间提供了因果联系。
