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.

Seoul National University · biorxiv

Paper

Abstract

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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Research summary

The paper claims that the chemical N-degron ATB1071 activates mitophagy and provides therapeutic benefits in models of mitochondrial neuropathies. The research addresses the activation of mitophagy, which is a critical process in combating age-related mitochondrial dysfunction, thus contributing to longevity research.

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