Stimulated protein degradation to promote mitochondrial function and neuronal survival

Targeted protein degradation is a promising modality to treat cancer or inflammation, but whether it can provide a similar benefit for disorders caused by pervasive protein dysregulation is unclear. We describe stimulated protein degradation (SPD) as a strategy that leverages agonists of stress-responsive E3 ubiquitin ligases to simultaneously eliminate multiple pathogenic factors. Specifically, we show that activators of the reductive stress response E3 CUL2^FEM1B boost degradation of multiple physiological substrates to improve mitochondrial import and electron transport chain assembly. In this manner, CUL2^FEM1B agonists preserve mitochondrial function and neuronal survival in models of neurodegenerative COX deficiency syndrome and Friedreich's ataxia. By activating E3 ligases that evolved to safeguard cellular integrity, SPD expands the use of compound-induced protein degradation to complex pathologies of high unmet need.