Abstract
BackgroundCells treated with hsp90 inhibitors exhibit pleiotropic changes, including an expansion of the mitochondrial compartment, accompanied by mitochondrial fragmentation and condensed mitochondrial morphology, with ultimate compromise of mitochondrial integrity and apoptosis.FindingsWe identified several mitochondrial oxidative phosphorylation complex subunits, including several encoded by mtDNA, that are upregulated by hsp90 inhibitors, without corresponding changes in mRNA abundance. Post-transcriptional accumulation of mitochondrial proteins observed with hsp90 inhibitors is also seen in cells treated with proteasome inhibitors. Detailed studies of the OSCP subunit of mitochondrial F1F0-ATPase revealed the presence of mono- and polyubiquitinated OSCP in mitochondrial fractions. We demonstrate that processed OSCP undergoes retrotranslocation to a trypsin-sensitive form associated with the outer mitochondrial membrane. Inhibition of proteasome or hsp90 function results in accumulation of both correctly targeted and retrotranslocated mitochondrial OSCP.ConclusionsCytosolic turnover of mitochondrial proteins demonstrates a novel connection between mitochondrial and cytosolic compartments through the ubiquitin-proteasome system. Analogous to defective protein folding in the endoplasmic reticulum, a mitochondrial unfolded protein response may play a role in the apoptotic effects of hsp90 and proteasome inhibitors.
Highlights
Hsp90 is an abundant cytosolic chaperone (1–2% of cytosolic protein) involved in the turnover, trafficking and activity of a large number and variety of client proteins
COLO 205 colon cancer cells treated with hsp90 inhibitors, including herbimycin A (HA), 17-allylamino-17-demethoxygeldanamycin (17-AAG) and radicicol, undergo terminal differentiation and apoptotic cell death within 72–96 h, preceded by dramatic changes to the mitochondrial compartment or chondriome [11] (Fig. 1 A and data not shown)
We determined whether expression of individual mitochondrial proteins changed in cells treated with hsp90 inhibitors (Fig. 3A)
Summary
Hsp is an abundant cytosolic chaperone (1–2% of cytosolic protein) involved in the turnover, trafficking and activity of a large number and variety of client proteins. These include membraneassociated and soluble protein kinases (many recognized as oncogenes) and transcription factors [1,2]. Cells treated with hsp inhibitors exhibit pleiotropic changes, including an expansion of the mitochondrial compartment, accompanied by mitochondrial fragmentation and condensed mitochondrial morphology, with ultimate compromise of mitochondrial integrity and apoptosis. Post-transcriptional accumulation of mitochondrial proteins observed with hsp inhibitors is seen in cells treated with proteasome inhibitors. Inhibition of proteasome or hsp function results in accumulation of both correctly targeted and retrotranslocated mitochondrial OSCP. Analogous to defective protein folding in the endoplasmic reticulum, a mitochondrial unfolded protein response may play a role in the apoptotic effects of hsp and proteasome inhibitors
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