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The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder
EMBO Reports ( IF 7.7 ) Pub Date : 2021-08-05 , DOI: 10.15252/embr.202051991
Esther Nuebel 1, 2, 3 , Jeffrey T Morgan 1, 2 , Sarah Fogarty 1, 2 , Jacob M Winter 2 , Sandra Lettlova 2 , Jordan A Berg 2 , Yu-Chan Chen 2 , Chelsea U Kidwell 2 , J Alan Maschek 2, 4, 5 , Katie J Clowers 6 , Catherine Argyriou 7 , Lingxiao Chen 8 , Ilka Wittig 9 , James E Cox 2, 4, 5 , Minna Roh-Johnson 2 , Nancy Braverman 7, 10 , Joshua Bonkowsky 11 , Steven P Gygi 6 , Jared Rutter 1, 2, 4
Affiliation  

Peroxisomal biogenesis disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs—Zellweger spectrum disorder (ZSD)—is caused by mutations in peroxin genes that result in both non-functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment. In order to understand the molecular basis of this inter-organellar relationship, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that peroxins were still expressed and a subset of them accumulated on the mitochondrial membrane, which resulted in gross mitochondrial abnormalities and impaired mitochondrial metabolic function. We showed that overexpression of ATAD1, a mitochondrial quality control factor, was sufficient to rescue several aspects of mitochondrial function in human ZSD fibroblasts. Together, these data suggest that aberrant peroxisomal protein localization is necessary and sufficient for the devastating mitochondrial morphological and metabolic phenotypes in ZSDs.

中文翻译:

齐薇格谱障碍线粒体功能障碍的生化基础

过氧化物酶体生物发生障碍 (PBD) 是过氧化物酶体生物发生和代谢的遗传疾病,其特征在于深刻的发育和神经表型。最严重的 PBD 类 - 齐薇格谱系障碍 (ZSD) - 是由过氧化物基因突变引起的,这些突变导致过氧化物酶体无功能和线粒体功能障碍。然而,尚不清楚有缺陷的过氧化物酶体如何导致线粒体损伤。为了了解这种细胞器间关系的分子基础,我们研究了 ZSD 模型系统中过氧化物酶体 mRNA 和蛋白质的命运。我们发现过氧化物仍然表达,其中一部分在线粒体膜上积累,导致线粒体严重异常和线粒体代谢功能受损。我们发现,线粒体质量控制因子 ATAD1 的过表达足以挽救人类 ZSD 成纤维细胞中线粒体功能的几个方面。总之,这些数据表明异常的过氧化物酶体蛋白定位对于 ZSD 中破坏性的线粒体形态和代谢表型是必要和充分的。
更新日期:2021-10-06
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