HSP60 chaperone deficiency disrupts the mitochondrial matrix proteome and dysregulates cholesterol synthesis

Cagla Cömert*, Kasper Kjær-Sørensen, Jakob Hansen, Jasper Carlsen, Jesper Just, Brandon F. Meaney, Elsebet Østergaard, Yonglun Luo, Claus Oxvig, Lisbeth Schmidt-Laursen, Johan Palmfeldt, Paula Fernandez-Guerra, Peter Bross

*Corresponding author for this work

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Abstract

Objective: Mitochondrial proteostasis is critical for cellular function. The molecular chaperone HSP60 is essential for cell function and dysregulation of HSP60 expression has been implicated in cancer and diabetes. The few reported patients carrying HSP60 gene variants show neurodevelopmental delay and brain hypomyelination. Hsp60 interacts with more than 260 mitochondrial proteins but the mitochondrial proteins and functions affected by HSP60 deficiency are poorly characterized. Methods: We studied two model systems for HSP60 deficiency: (1) engineered HEK cells carrying an inducible dominant negative HSP60 mutant protein, (2) zebrafish HSP60 knockout larvae. Both systems were analyzed by RNASeq, proteomics, and targeted metabolomics, and several functional assays relevant for the respective model. In addition, skin fibroblasts from patients with disease-associated HSP60 variants were analyzed by proteomics. Results: We show that HSP60 deficiency leads to a differentially downregulated mitochondrial matrix proteome, transcriptional activation of stress responses, and dysregulated cholesterol biosynthesis. This leads to lipid accumulation in zebrafish knockout larvae. Conclusions: Our data provide a compendium of the effects of HSP60 deficiency on the mitochondrial matrix proteome. We show that HSP60 is a master regulator and modulator of mitochondrial functions and metabolic pathways. HSP60 dysfunction also affects cellular metabolism and disrupts the integrated stress response. The effect on cholesterol synthesis explains the effect of HSP60 dysfunction on myelination observed in patients carrying genetic variants of HSP60.

Original languageEnglish
Article number102009
JournalMolecular Metabolism
Volume88
Number of pages20
ISSN2212-8778
DOIs
Publication statusPublished - 2024

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© 2024 Aarhus University

Keywords

  • Chaperone
  • Cholesterol
  • Folding
  • HSP60
  • HSPD1
  • Mitochondria
  • Myelination
  • Proteomics
  • Transcriptomics
  • Zebrafish

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