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Cited by 3Autophagy in Disease and TherapyRedox biology and oxidative stressMetabolism and Genetic Disorders

Depletion of LONP2 unmasks differential requirements for peroxisomal function between cell types and in cholesterol metabolism.

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Yamashita, Akihiro, Ignatenko, Olesia, Nguyen, Mai, Lambert, Raphaëlle, Watt, Kathleen, Daneault, Caroline, Robillard-Frayne, Isabelle, Topisirovic, Ivan +2 more·2023·Biology Direct
DOI 10.1186/s13062-023-00416-3PMC PMC10515011

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Abstract

Peroxisomes play a central role in tuning metabolic and signaling programs in a tissue- and cell-type-specific manner. However, the mechanisms by which the status of peroxisomes is communicated and integrated into cellular signaling pathways are not yet understood. Herein, we report the cellular responses to peroxisomal proteotoxic stress upon silencing the peroxisomal protease/chaperone LONP2. Depletion of LONP2 triggered the accumulation of its substrate TYSND1 protease, while the overall expression of peroxisomal proteins, as well as TYSND1-dependent ACOX1 processing appeared normal, reflecting early stages of peroxisomal proteotoxic stress. Consequently, the alteration of peroxisome size and numbers, and luminal protein import failure was coupled with induction of cell-specific cellular stress responses. Specific to COS-7 cells was a strong activation of the integrated stress response (ISR) and upregulation of ribosomal biogenesis gene expression levels. Common changes between COS-7 and U2OS cell lines included repression of the retinoic acid signaling pathway and upregulation of sphingolipids. Cholesterol accumulated in the endomembrane compartments in both cell lines, consistent with evidence that peroxisomes are required for cholesterol flux out of late endosomes. These unexpected consequences of peroxisomal stress provide an important insight into our understanding of the tissue-specific responses seen in peroxisomal disorders.

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  • Peroxisomes were proposed to function as hubs for the transfer of cholesterol to the ER for degradation.

    “Alternatively, peroxisomes were proposed to function as hubs for the transfer of cholesterol to the ER for degradation (Chu et al., 2015; Yamashita et al., 2023).”

    From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Yamashita et al., 2023

    The Discussion reports that peroxisomes form contacts with lysosomes that facilitate cholesterol flux to the ER, and the Results likewise discuss cholesterol movement from late endosomes to the ER (page not provided). Neither passage says the cholesterol is transferred there for degradation; the degradation mentioned in the Results concerns the ER protein INSIG1, not cholesterol. (LLM, conf=0.87)

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Cited by

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Authors
Yamashita, A., Ignatenko, O., Nguyen, M., Lambert, R., Watt, K., Daneault, C., Robillard-Frayne, I., Topisirovic, I., Rosiers, C. D., & McBride, H. M.
Affiliations
  • Montreal Neurological Institute and Hospital (CA)
  • Institute for Research in Immunology and Cancer (CA)
  • Karolinska Institutet (SE)
  • Montreal Heart Institute (CA)
Corresponding author
McBride, Heidi M.
ORCID
Venue
Biology Direct
Publisher
Springer Science and Business Media LLC
Published
2023-09-22
Volume
18
Issue
1
Pages
60-60
ISSN
1745-6150 (ISSN-L)
DOI
10.1186/s13062-023-00416-3
PMC
PMC10515011
OpenAlex
W4386945539
Cited by
3
References
3
Citations by year
2025: 1 · 2024: 2
FWCI
0.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Biology Direct (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Canadian Institutes of Health Research (PJT-162183)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
peroxisomes, integrated stress response, ribosome biogenesis, retinoic acid signaling, sphingolipids, cholesterol metabolism, late endosomes, peroxisomal disorders
MeSH terms
Peptide Hydrolases, Endosomes, Ribosomes, Signal Transduction, Up-Regulation

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