The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder

• Published in: EMBO reports 2021-10, Vol.22 (10), p.e51991-n/a
• Main Authors: Nuebel, Esther, Morgan, Jeffrey T, Fogarty, Sarah, Winter, Jacob M, Lettlova, Sandra, Berg, Jordan A, Chen, Yu-Chan, Kidwell, Chelsea U, Maschek, J Alan, Clowers, Katie J, Argyriou, Catherine, Chen, Lingxiao, Wittig, Ilka, Cox, James E, Roh-Johnson, Minna, Braverman, Nancy, Bonkowsky, Joshua, Gygi, Steven P, Rutter, Jared
• Format: Article
• Language: English
• Subjects: Abnormalities; Biosynthesis; Cytology; Disorders; EMBO21; EMBO24; EMBO57; Evolution; Fibroblasts; Genetic disorders; Humans; Localization; Membranes; Metabolism; Mitochondria; Mitochondria - genetics; mitochondrial quality control; Morphology; Mutation; Peroxin; Peroxins - metabolism; peroxisomal biogenesis disorder; Peroxisomal Disorders - genetics; Peroxisomal Disorders - metabolism; peroxisomal import; Peroxisomes; Peroxisomes - metabolism; Phenotypes; Proteins; Quality control; Transcription; Zellweger Syndrome - genetics; Zellweger Syndrome - metabolism
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202051991

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. Synopsis How peroxisomal biogenesis disorders lead to mitochondrial dysfunction is not well understood. This study reveals that peroxisomal proteins mislocalize to the mitochondria, thereby disrupting mitochondrial function. The mitochondrial quality control protein ATAD1 can rescue this defect. Peroxin transcription and translation is unperturbed by loss of peroxisomes. Several peroxins (Pex13, Pex11, Pex14, Pex2, Pex17, Pex25) mislocalize to the mitochondrial outer membrane. Mislocalized peroxins are able to form a subassembly of the peroxisomal importomer on mitochondria, which interferes with mitochondrial function. The mitochondrial extractase ATAD1 can remove peroxins from the mitochondrial membrane, which is sufficient to restore mitochondrial morphology, respiration, and metabolism in cells derived from ZSD patients. Graphical Abstract How peroxisomal biogenesis disorders lead to mitochondrial dysfunction is not well understood. This study reveals that peroxisomal proteins mislocalize to the mitochondria, thereby disrupting mitochondrial function. The mitochondrial quality control protein ATAD1 can rescue this defect.