The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder

Nuebel, Esther; Morgan, Jeffrey T.; Fogarty, Sarah; Winter, Jacob M.; Lettlová, Sandra; Berg, Jordan A.; Chen, Yuchan; 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 L.; Gygi, Steven P.; Rutter, Jared

doi:10.15252/embr.202051991

Cited by 32 publications

(57 citation statements)

References 98 publications

(114 reference statements)

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“…Likewise, we cannot rule out that the depletion of some precursors could derive from transcriptional effects. However, we consider this unlikely, as previous transcriptomics studies revealed that solely the absence of peroxisomes does not generally result in global mRNA expression changes [ 57 ].…”

Section: Discussionmentioning

confidence: 96%

Quantitative Proteomics and Differential Protein Abundance Analysis after the Depletion of PEX3 from Human Cells Identifies Additional Aspects of Protein Targeting to the ER

Zimmermann

Lang

Lerner

et al. 2021

IJMS

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Protein import into the endoplasmic reticulum (ER) is the first step in the biogenesis of around 10,000 different soluble and membrane proteins in humans. It involves the co- or post-translational targeting of precursor polypeptides to the ER, and their subsequent membrane insertion or translocation. So far, three pathways for the ER targeting of precursor polypeptides and four pathways for the ER targeting of mRNAs have been described. Typically, these pathways deliver their substrates to the Sec61 polypeptide-conducting channel in the ER membrane. Next, the precursor polypeptides are inserted into the ER membrane or translocated into the ER lumen, which may involve auxiliary translocation components, such as the TRAP and Sec62/Sec63 complexes, or auxiliary membrane protein insertases, such as EMC and the TMCO1 complex. Recently, the PEX19/PEX3-dependent pathway, which has a well-known function in targeting and inserting various peroxisomal membrane proteins into pre-existent peroxisomal membranes, was also found to act in the targeting and, putatively, insertion of monotopic hairpin proteins into the ER. These either remain in the ER as resident ER membrane proteins, or are pinched off from the ER as components of new lipid droplets. Therefore, the question arose as to whether this pathway may play a more general role in ER protein targeting, i.e., whether it represents a fourth pathway for the ER targeting of precursor polypeptides. Thus, we addressed the client spectrum of the PEX19/PEX3-dependent pathway in both PEX3-depleted HeLa cells and PEX3-deficient Zellweger patient fibroblasts by an established approach which involved the label-free quantitative mass spectrometry of the total proteome of depleted or deficient cells, as well as differential protein abundance analysis. The negatively affected proteins included twelve peroxisomal proteins and two hairpin proteins of the ER, thus confirming two previously identified classes of putative PEX19/PEX3 clients in human cells. Interestingly, fourteen collagen-related proteins with signal peptides or N-terminal transmembrane helices belonging to the secretory pathway were also negatively affected by PEX3 deficiency, which may suggest compromised collagen biogenesis as a hitherto-unknown contributor to organ failures in the respective Zellweger patients.

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Section: Discussionmentioning

confidence: 96%

Quantitative Proteomics and Differential Protein Abundance Analysis after the Depletion of PEX3 from Human Cells Identifies Additional Aspects of Protein Targeting to the ER

Zimmermann

Lang

Lerner

et al. 2021

IJMS

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show abstract

“…Likewise, we cannot rule out that the depletion of some precursors could derive from transcriptional effects. However, we consider this unlikely since previous transcriptomics studies revealed that solely the absence of peroxisomes does not generally result in global mRNA expression changes [57].…”

Section: Discussionmentioning

confidence: 92%

Quantitative Proteomics and Differential Protein Abundance Analysis after Depletion of PEX3 from Human Cells Identifies Additional Aspects of Protein Targeting to the ER

Zimmermann¹,

Lang²,

Lerner³

et al. 2021

Preprint

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Protein import into the endoplasmic reticulum (ER) is the first step in the biogenesis of about 10,000 different soluble and membrane proteins in humans. It involves co- or post-translational targeting of precursor polypeptides to the ER and their subsequent membrane insertion or translocation. So far, three pathways for ER targeting of precursor polypeptides plus four pathways for ER targeting of mRNAs were described. Typically, these pathways deliver their substrates to the Sec61 polypeptide-conducting channel in the ER membrane. Next, the precursor polypeptides are inserted into the ER membrane or translocated into the ER lumen, which may involve auxiliary translocation components, such as the TRAP and Sec62/Sec63 complexes, or auxiliary membrane protein insertases, such as EMC and the TMCO1 complex. Recently, the PEX19/PEX3-dependent pathway, which has a well-known function in targeting and inserting various peroxisomal membrane proteins into pre-existent peroxisomal membranes, was also found to act in targeting and, putatively, inserting monotopic hairpin proteins into the ER. These either remain in the ER as resident ER membrane proteins or are pinched off from the ER as components of new lipid droplets. Therefore, the question arose if this pathway may play a more general role in ER protein targeting, i.e. represents a fourth pathway for ER targeting of precursor polypeptides. Thus, we addressed the client spectrum of the PEX19/PEX3-dependent pathway in both PEX3-depleted HeLa cells and PEX3-deficient Zellweger patient fibroblasts by an established approach, which involves label-free quantitative mass spectrometry of the total proteome of depleted or deficient cells and differential protein abundance analysis. The negatively affected proteins included twelve peroxisomal proteins and two hairpin proteins of the ER, thus confirming two previously identified classes of putative PEX19/PEX3-clients in human cells. Interestingly, fourteen collagen-related proteins with signal peptides or N-terminal transmembrane helices and belonging to the secretory pathway were also negatively affected by PEX3-deficiency, which may suggest compromised collagen biogenesis as a hitherto unknown contributor to organ failures in the respective Zellweger patients.

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“…In a recent CP study of peroxisome-deficient cells using peroxins deletion strains of S. cerevisiae as a model system and fibroblasts from a Zellweger syndrome patient, Nübel and co-workers linked accumulation of miss-targeted peroxisomal membrane proteins into mitochondria to metabolic and morphological abnormalities of this organelle ( Nuebel et al, 2021 ). Complexome profiles of yeast strains lacking peroxisomes showed formation of the docking subassembly of the peroxisomal importomer complex in mitochondria, explaining also the incorporation of peroxisomal matrix proteins to this subcellular compartment.…”

Section: Complexome Profiling: Perspectivesmentioning

confidence: 99%

Complexome Profiling—Exploring Mitochondrial Protein Complexes in Health and Disease

Cabrera‐Orefice

Potter²,

Evers

et al. 2022

Front. Cell Dev. Biol.

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Complexome profiling (CP) is a state-of-the-art approach that combines separation of native proteins by electrophoresis, size exclusion chromatography or density gradient centrifugation with tandem mass spectrometry identification and quantification. Resulting data are computationally clustered to visualize the inventory, abundance and arrangement of multiprotein complexes in a biological sample. Since its formal introduction a decade ago, this method has been mostly applied to explore not only the composition and abundance of mitochondrial oxidative phosphorylation (OXPHOS) complexes in several species but also to identify novel protein interactors involved in their assembly, maintenance and functions. Besides, complexome profiling has been utilized to study the dynamics of OXPHOS complexes, as well as the impact of an increasing number of mutations leading to mitochondrial disorders or rearrangements of the whole mitochondrial complexome. Here, we summarize the major findings obtained by this approach; emphasize its advantages and current limitations; discuss multiple examples on how this tool could be applied to further investigate pathophysiological mechanisms and comment on the latest advances and opportunity areas to keep developing this methodology.

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The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder

Cited by 32 publications

References 98 publications

Quantitative Proteomics and Differential Protein Abundance Analysis after the Depletion of PEX3 from Human Cells Identifies Additional Aspects of Protein Targeting to the ER

Quantitative Proteomics and Differential Protein Abundance Analysis after the Depletion of PEX3 from Human Cells Identifies Additional Aspects of Protein Targeting to the ER

Quantitative Proteomics and Differential Protein Abundance Analysis after Depletion of PEX3 from Human Cells Identifies Additional Aspects of Protein Targeting to the ER

Complexome Profiling—Exploring Mitochondrial Protein Complexes in Health and Disease

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