Mapping stress-responsive signaling pathways induced by mitochondrial proteostasis perturbations

Area of Science:

• Cellular Biology
• Molecular Biology
• Genetics

Background:

• Mitochondrial proteostasis is crucial for cellular health, and its disruption is linked to various diseases.
• Understanding how cells respond to mitochondrial stress is vital for developing therapeutic strategies.
• Several stress-responsive pathways, including the integrated stress response (ISR), heat shock response (HSR), and oxidative stress response (OSR), are implicated in cellular stress management.

Purpose of the Study:

• To define the specific stress signaling pathways activated by chronic mitochondrial proteostasis perturbations.
• To investigate the role of the integrated stress response (ISR) in response to mitochondrial stress.

Main Methods:

• Utilized published Perturb-seq datasets from K562 cells with CRISPRi-mediated depletion of mitochondrial proteostasis factors.
• Monitored the expression of gene sets downstream of ISR, HSR, and OSR to identify activated pathways.
• Analyzed the impact of depleting other mitochondria-localized proteins on stress pathway activation.

Main Results:

• The integrated stress response (ISR) was preferentially activated in response to chronic, genetically induced mitochondrial proteostasis stress.
• No other major stress-responsive pathways (HSR, OSR) showed significant activation under these conditions.
• Depletion of other mitochondrial proteins also demonstrated a preferential activation of the ISR.

Conclusions:

• The gene set profiling approach is effective for probing stress signaling pathways activated by organelle-specific perturbations.
• The integrated stress response (ISR) is identified as the predominant signaling pathway activated during chronic disruption of mitochondrial proteostasis.