BNIP3L/NIX-mediated mitophagy limits Alzheimer’s disease pathology and preserves neuronal function
Year: 2026
Type: preprint
Abstract: Defective mitophagy is emerging as a key contributor to Alzheimer’s 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 Aβ 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.
Authors: Yuan Li, Christina ploumi, Christiane Volbracht, Weihua Tian, Nefeli Kalogeraki, Katerina Kitopoulou, Claudia Carvalho Navarro, Zhiquan Li, Nicolas Cherbuin, Leticia Camargo Tavares, Zilu Ye, Aleksander J. Norwak, Satyan Chintawar, M Zameel Cader, Laura Berliocchi, Steffen Goletz, Vilhelm A. Bohr, Kristine Freude, Konstantinos Palikaras, Lene Juel Rasmussen
Institutions: University of Copenhagen, National and Kapodistrian University of Athens, Lundbeck (Denmark), Technical University of Denmark, Australian National University, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou Institute of Systems Medicine, University of Oxford, Magna Graecia University
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7223005219