Stimulated protein degradation to promote mitochondrial function and neuronal survival.

Activating the reductive stress response E3 ligase CUL2 FEM1B boosts degradation of multiple physiological substrates, improving mitochondrial import and electron transport chain assembly.

• Why it matters: Targeted protein degradation is promising for cancer or inflammation, but its ability to help disorders driven by widespread protein dysregulation is unclear.
• What they did: The study used CUL2 FEM1B agonists to stimulate SPD and measured effects on mitochondrial import, electron transport chain assembly, and neuronal survival in neurodegenerative COX deficiency syndrome and Friedreich's ataxia models.
• The result: In both neurodegenerative COX deficiency syndrome and Friedreich's ataxia models, CUL2 FEM1B agonists preserved mitochondrial function and neuronal survival, supporting SPD for complex protein-dysregulation disorders.

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