In situ characterization of mitochondrial Hsp60-Hsp10 chaperone complex under folding stress

Area of Science:

• Cell Biology
• Structural Biology
• Biochemistry

Background:

• Mitochondrial proteostasis is essential for cellular function.
• Disruption triggers the mitochondrial unfolded protein response (UPRmt).
• The role of chaperones like mtHsp60-Hsp10 in mitigating stress is not fully understood.

Purpose of the Study:

• To elucidate the in situ structure and function of the mtHsp60-Hsp10 complex under protein-folding stress.
• To understand the mechanisms by which chaperones alleviate mitochondrial proteostasis stress.

Main Methods:

• Correlated cryo-electron tomography (cryo-ET).
• Subtomogram analysis.
• Knockdown experiments.

Main Results:

• Protein-folding stress induces mitochondrial morphological changes and aggregation.
• The mtHsp60-Hsp10 complex increases in abundance and clusters spatially.
• In situ structural analysis revealed distinct conformational states (football, half-football, bullet-like) of the complex.
• The complex encapsulates unfolded substrates via hydrophobic interactions.
• mtHsp60-Hsp10 knockdown exacerbates folding stress and activates mitophagy.

Conclusions:

• The study defines the in situ structural properties of the mtHsp60-Hsp10 complex.
• Provides mechanistic insight into how the complex safeguards mitochondrial proteostasis.
• Highlights the critical role of mtHsp60-Hsp10 in managing mitochondrial protein-folding stress.