2. Academic Validation
  3. APOE4 impairs Nrf2-PINK1/Parkin-dependent mitochondrial clearance through disrupted antioxidant and mitophagy signaling

APOE4 impairs Nrf2-PINK1/Parkin-dependent mitochondrial clearance through disrupted antioxidant and mitophagy signaling

  • Free Radic Biol Med. 2025 Nov 21:243:245-259. doi: 10.1016/j.freeradbiomed.2025.11.040.
Firoz Akhter 1,  Asma Akhter 1,  Donghui Zhu 2
Affiliations

Affiliations

  • 1 Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, 11794, United States.
  • 2 Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, 11794, United States; Neuroscience Graduate Program, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, United States. Electronic address: [email protected].
PMID: 41275935 DOI: 10.1016/j.freeradbiomed.2025.11.040
Abstract

APOE4, the strongest genetic risk factor for sporadic Alzheimer's disease (AD), is closely associated with mitochondrial dysfunction, yet the mechanisms remain poorly defined. We identify a previously unrecognized failure of the Nrf2-PINK1/Parkin axis in APOE4 neurons that compromises mitochondrial quality control. Unlike APOE3, APOE4 neurons fail to activate PINK1/Parkin-dependent Mitophagy under stress, a defect compounded by impaired Nrf2 signaling and weakened antioxidant defenses. In vivo, APOE4 mice show age-dependent collapse of this pathway, correlating with progressive mitochondrial dysfunction and disrupted mito-nuclear communication. Pharmacological activation of Nrf2 or PINK1 restores mitochondrial clearance, highlighting the axis as a druggable node. These findings provide a mechanistic link between APOE4 and mitochondrial failure, establishing the Nrf2-PINK1/Parkin pathway as a critical driver of neurodegeneration and a promising target for therapeutic intervention in AD.

Keywords

APOE4; Alzheimer's disease (AD); Mito-nuclear communication; Mitochondrial stress; Mitophagy; Nrf2-PINK/Parkin.

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