Special Biochemistry Seminar

Stress response pathways detect and alleviate adverse conditions to safeguard cellular homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health. How stress responses are turned off at the right time remains poorly understood. We report a ubiquitin-dependent mechanism to silence the response to mitochondrial protein import stress. We identify an E3 ligase complex mutated in neurodegenerative disease that degrades both unimported precursors and stress response components, coupling stress response silencing to stress resolution. Pharmacological silencing rescues cells despite failed stress resolution, underscoring the importance of silencing and suggesting a treatment roadmap for neurodegeneration originating from mitochondrial import defects.