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Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
07:57

Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors

Published on: January 20, 2023

Hsp90 inhibition decreases mitochondrial protein turnover

Daciana H Margineantu1, Christine B Emerson, Dolores Diaz

  • 1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

Plos One
|October 25, 2007
PubMed
Abstract

Insights

Heat shock protein 90 (HSP90) inhibitors cause mitochondrial issues and protein buildup. This suggests a link between mitochondrial and cytosolic protein turnover via the ubiquitin-proteasome system.

Area of Science:

  • Mitochondrial Biology
  • Cellular Stress Response
  • Protein Degradation

Background:

  • HSP90 inhibitors induce significant cellular changes, including mitochondrial expansion, fragmentation, and morphological alterations.
  • These changes ultimately compromise mitochondrial integrity and lead to apoptosis.

Purpose of the Study:

  • To investigate the post-transcriptional regulation of mitochondrial proteins under HSP90 inhibition.
  • To explore the role of the ubiquitin-proteasome system in mitochondrial protein turnover.

Main Methods:

  • Analysis of mitochondrial oxidative phosphorylation complex subunits.
  • Detection of ubiquitinated proteins in mitochondrial fractions.
  • Studies on the retrotranslocation of mitochondrial proteins.

Main Results:

  • Upregulation of mitochondrial oxidative phosphorylation complex subunits, including mtDNA-encoded ones, without mRNA changes.
  • Post-transcriptional accumulation of mitochondrial proteins, similar to proteasome inhibitor effects.
  • Identification of ubiquitinated OSCP undergoing retrotranslocation; accumulation of both correctly targeted and retrotranslocated OSCP upon proteasome or HSP90 inhibition.

Conclusions:

  • Cytosolic turnover of mitochondrial proteins reveals a novel link between mitochondrial and cytosolic compartments via the ubiquitin-proteasome system.
  • A mitochondrial unfolded protein response may contribute to apoptosis induced by HSP90 and proteasome inhibitors, mirroring ER stress responses.

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