BNIP3L/NIX-mediated mitophagy limits Alzheimer disease pathology and preserves neuronal function
- 1Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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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BibTeX
@misc{li2026bnip3lnixmediated,
title = {{BNIP3L/NIX-mediated mitophagy limits Alzheimer disease pathology and preserves neuronal function}},
author = {Y. Li and C. Ploumi and C. Volbracht and W. TIan and N. Kalogeraki and K. Kitopoulou and C. C. Navarro and Z. Li and N. Cherbuin and L. Camargo and Z. Ye and A. J. Nowak and S. Chintawar and M. Z. Cader and L. Berliocchi and S. Goletz and V. Bohr and K. Freude and K. Pakalikaras and L. Rasmussen},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.18.759942},
url = {https://www.biorxiv.org/content/10.64898/2026.10.18.759942v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - BNIP3L/NIX-mediated mitophagy limits Alzheimer disease pathology and preserves neuronal function
AU - Y. Li
AU - C. Ploumi
AU - C. Volbracht
AU - W. TIan
AU - N. Kalogeraki
AU - K. Kitopoulou
AU - C. C. Navarro
AU - Z. Li
AU - N. Cherbuin
AU - L. Camargo
AU - Z. Ye
AU - A. J. Nowak
AU - S. Chintawar
AU - M. Z. Cader
AU - L. Berliocchi
AU - S. Goletz
AU - V. Bohr
AU - K. Freude
AU - K. Pakalikaras
AU - L. Rasmussen
PY - 2026
DA - 2026/10/18
PB - bioRxiv
DO - 10.64898/2026.10.18.759942
UR - https://www.biorxiv.org/content/10.64898/2026.10.18.759942v1
AB - 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.
ER -