Chemical activation of mitophagy via the N-degron pathway alleviates mitochondrial neuropathies
Kwon, S. C.; Kim, B.-S.; Kim, H.; Kang, D. E.; Lee, G. E.; Jung, E. J.; Lee, M. J.; Son, Y. S.; Park, D.-h.; Park, D. Y.; Lee, J.; Cho, E. H.; Kim, S. B.; Heo, A. J.; Suh, Y. H.; Jang, W.-D.; Han, D.; Ji, C. H.; Ahn, J.-Y.; Kwon, Y. T.
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Pharmacological activation of mitophagy offers a promising strategy to eliminate dysfunctional mitochondria that drive neurodegenerative and ischemic pathologies; however, the clinical translation of mitophagy inducers remains challenging. Here, we developed ATB1071, an orally bioavailable chemical N-degron that activates p62-mediated mitophagy through both Parkin-independent pathways involving NIPSNAP1 and NIPSNAP2, and a Parkin-dependent pathway involving the substrate EBP1/PA2G4. In Ndufs4-/- mice, a Leigh syndrome (LS) model, ATB1071 induced mitophagy in the brain and exerted therapeutic benefits by reducing neuroinflammation, improving neuromuscular coordination, and extending lifespan. In cerebral ischemia-reperfusion (IR) model mice, ATB1071 markedly reduced infarct volume and neuronal death, and ameliorated multiple behavioral deficits through EBP1-dependent mitophagy. Pharmacokinetic (PK) and toxicological evaluation identify ATB1071 as a promising preclinical therapeutic candidate for alleviating mitochondria-associated neurological injury.
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