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.

doi:10.64898/2026.02.19.706908

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bioRxiv · 10.64898/2026.02.19.706908

Chemical activation of mitophagy via the N-degron pathway alleviates mitochondrial neuropathies

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Abstract

Pharmacological activation of mitophagy offers a promising strategy to eliminate dysfunctional mitochondria. We previously identified the autophagy receptor p62/SQSTM1 as an N-recognin whose activity is enhanced by Arg/N-degrons. Here, we show that Arg/N-degrons generated by ATE1-encoded R-transferase regulate p62-mediated mitophagy by promoting its recruitment to damaged mitochondria. Structural modification of Arg/N-degrons yielded ATB1071, a 443.5-Da orally bioavailable compound that activates p62 and induces stress-selective 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 muscle strength and neuromuscular coordination, and extending lifespan. In cerebral ischemia-reperfusion (IR) model mice, ATB1071 reduced infarct volume and neuronal death, and ameliorated multiple behavioral deficits through EBP1-dependent mitophagy. Pharmacokinetic (PK) and toxicological analyses support ATB1071 as a preclinical candidate for mitochondria-associated neurological injury.

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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.. 2026-02-20. Chemical activation of mitophagy via the N-degron pathway alleviates mitochondrial neuropathies. https://doi.org/10.64898/2026.02.19.706908

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