REVIEW article
Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
Volume 17 - 2025 | doi: 10.3389/fnagi.2025.1544241
This article is part of the Research TopicMolecular mechanisms of neurodegenerationView all 9 articles
Review of FUNDC1-mediated mitochondrial autophagy in Alzheimer's disease
Provisionally accepted
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Mitochondrial autophagy is a critical quality control mechanism that eliminates dysfunctional mitochondria to maintain cellular homeostasis. Among receptor-dependent mitophagy pathways, FUN14 domain-containing 1 (FUNDC1)—a mitochondrial outer membrane protein harboring an LC3-interacting region (LIR)—plays a central role by directly binding to LC3 under stress conditions, thereby initiating autophagosome encapsulation of damaged organelles. Emerging evidence implicates FUNDC1 dysregulation in neurodegenerative diseases, particularly Alzheimer’s disease (AD), where defective mitophagy exacerbates hallmark pathologies including Aβ plaque deposition and hyperphosphorylated Tau-driven neurofibrillary tangles. Despite advances, the molecular interplay between FUNDC1 phosphorylation states (e.g., Ser13/Ser17/Tyr18) and AD progression remains poorly defined. This review systematically examines FUNDC1’s dual regulatory role in mitophagy, its mechanistic links to Aβ and Tau pathologies, and the therapeutic potential of targeting FUNDC1-associated kinases (e.g., ULK1, CK2) or downstream effectors (e.g., DRP1, OPA1) to counteract mitochondrial dysfunction in AD. By synthesizing recent preclinical and clinical findings, we aim to bridge the gap between FUNDC1 biology and AD therapeutics, highlighting actionable nodes for drug development.
Keywords: Alzheimer's disease, FUNDC1 signaling pathway, Mitochondrial autophagy, Neurodegenerative Diseases, signaling molecules
Received: 12 Dec 2024; Accepted: 28 Apr 2025.
Copyright: © 2025 Shi, Guo, Ning, Zhang, Liu, Liu and Wei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Meixia Liu, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
Yun Wei, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
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