2. Academic Validation
  3. Hv1 inhibition rescues AD pathology by restoring microglial mitochondrial function and enhancing mitochondrial transfer

Hv1 inhibition rescues AD pathology by restoring microglial mitochondrial function and enhancing mitochondrial transfer

  • Exp Mol Med. 2025 Dec;57(12):2833-2851. doi: 10.1038/s12276-025-01593-z.
Jiayuan Lin # 1,  Huayun Han # 2,  Kexin Wu # 1,  Xingyu Wu 1,  Juwen Shen 2,  Yiqing Mo 3,  Qiansen Zhang 2,  Huaiyu Yang 4,  Zhihua Yu 5
Affiliations

Affiliations

  • 1 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
  • 3 Suzhou Institute of Drug Innovation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Suzhou, China.
  • 4 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. hyyang@bio.ecnu.edu.cn.
  • 5 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. yuzhihua@shsmu.edu.cn.
  • # Contributed equally.
PMID: 41402464 DOI: 10.1038/s12276-025-01593-z
Abstract

Hyperphosphorylated tau aggregation and neuroinflammation are hallmark pathologies of Alzheimer's disease (AD), with microglia playing a critical role in modulating these processes through maintaining immune homeostasis and clearing pathological tau, both of which depend on mitochondrial health. However, the mechanisms underlying microglial mitochondrial dysfunction in AD remain poorly understood, limiting therapeutic development. Hydrogen voltage-gated channel 1 (Hv1), expressed in microglia within the central nervous system, regulates intracellular pH and Reactive Oxygen Species generation. Here we observe that Hv1 is upregulated in activated microglia in AD mouse models. Remarkably, Hv1 contributes to electron transport chain abnormalities, leading to mitochondrial oxidative stress, loss of mitochondrial membrane potential, impaired ATP production and deficient Mitophagy in tau pathology. These deficits impair tau clearance through phagocytosis and Autophagy but can be significantly reversed by the Hv1-specific inhibitor YHV98-4. Furthermore, YHV98-4 enhances microglia-to-neuron mitochondrial transfer, promoting the delivery of functional mitochondria to rescue neuronal damage and improve cognitive function. Collectively, our study underscores the pivotal role of Hv1 in microglial mitochondrial dysfunction in AD and identifies YHV98-4 as a promising therapeutic candidate.

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