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The biochemical basis of mitochondrial dysfunctionin Zellweger Spectrum Disorder

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Joao Paulo

LAB HEAD: Jared Rutter

PROVIDER: PXD025595 | Pride | 2021-05-10

REPOSITORIES: Pride

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			Action	DRS
	208102_m07923_kc_mitop_01.mzIdentML	Mzid
	208110_m07924_kc_mitop_02.mzIdentML	Mzid
	208129_m07925_kc_mitop_03.mzIdentML	Mzid
	208130_m07926_kc_mitop_04.mzIdentML	Mzid
	208131_m07927_kc_mitop_05.mzIdentML	Mzid

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