BNIP3L/NIX-mediated mitophagy limits Alzheimer disease pathology and preserves neuronal function

Li, Y.; Ploumi, C.; Volbracht, C.; TIan, W.; Kalogeraki, N.; Kitopoulou, K.; Navarro, C. C.; Li, Z.; Cherbuin, N.; Camargo, L.; Ye, Z.; Nowak, A. J.; Chintawar, S.; Cader, M. Z.; Berliocchi, L.; Goletz, S.; Bohr, V.; Freude, K.; Pakalikaras, K.; Rasmussen, L.

doi:10.64898/2026.10.18.759942

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bioRxiv · 10.64898/2026.10.18.759942

BNIP3L/NIX-mediated mitophagy limits Alzheimer disease pathology and preserves neuronal function

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Abstract

Defective mitophagy is emerging as a key contributor to Alzheimer disease (AD), but the neuronal pathways governing mitochondrial clearance and their contribution to disease progression remain poorly understood. Here, we identify BNIP3L/NIX-dependent mitophagy as a conserved neuronal quality control pathway that maintains mitochondrial fitness and constrains AD-associated proteotoxicity. Loss of BNIP3L/NIX or its C. elegans orthologue DCT-1 impaired basal and stressed-induced mitophagy, disrupted mitochondrial homeostasis, enhanced Tau and Amyloid-beta pathology and compromised neuronal network, synaptic and behavioral function across human neuronal and in vivo models. Conversely, restoring BNIP3L/NIX and DCT-1 activity improved neuronal function under proteotoxic stress in vivo, reduced disease-associated Tau phosphorylation in human neurons and markedly suppressed seeded Tau aggregation in primary mouse neurons. Together, these findings identify BNIP3L/NIX-mediated mitophagy as a mechanistic link between mitochondrial quality control, proteostasis and neuronal function, and establish its restoration as a potential strategy for counteracting AD-associated pathology.

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Li, Y., Ploumi, C., Volbracht, C., TIan, W., Kalogeraki, N., Kitopoulou, K., Navarro, C. C., Li, Z., Cherbuin, N., Camargo, L., Ye, Z., Nowak, A. J., Chintawar, S., Cader, M. Z., Berliocchi, L., Goletz, S., Bohr, V., Freude, K., Pakalikaras, K., Rasmussen, L.. 2026-10-20. BNIP3L/NIX-mediated mitophagy limits Alzheimer disease pathology and preserves neuronal function. https://doi.org/10.64898/2026.10.18.759942

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