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Paranodal instability driven by axonal mitochondrial accumulation in ischemic demyelination and cognitive decline

Molecular Psychiatry volume 30, pages 3502–3515 (2025)Cite this article

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Abstract

Background

Subcortical ischemic demyelination is the primary cause of vascular cognitive impairment in the elderly. However, its underlying mechanisms remain elusive.

Methods

Using a bilateral common carotid artery stenosis (BACS) mouse model and an in vitro cerebellar slice model treated with low glucose-low oxygen (LGLO), we investigated a novel mechanism of vascular demyelination.

Results

This work identified syntaphilin-mediated docking of mitochondria as the initial event preceding ischemic demyelination. This axonal insult drives paranodal retraction, myelin instability, and subsequent cognitive impairment through excessive oxidation of protein 4.1B by mitochondrial ROS. Syntaphilin knockdown reestablished the balance of mitochondrial axoplasmic transport, reduced axonal ROS burden, and consequently decreased the abnormal oxidation of protein 4.1B, an essential component that secures the Caspr1/contactin-1/NF155 complex tethered to the axonal cytoskeleton βII-Spectrin within paranodes. This ultimately protected the paranodal structure and myelin and improved cognitive function.

Conclusions

Our findings reveal a distinct pathological characteristic of ischemic demyelination and highlight the therapeutic potential of modulating axonal mitochondrial mobility to stabilize myelin structures and improve vascular cognitive impairment.

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Fig. 1: Axonal mitochondrial accumulation precedes hypoperfusion-induced demyelination.
Fig. 2: Early axonal mitochondrial accumulation and paranodal instability precede ischemic demyelination.
Fig. 3: Alleviating mitochondrial excessive accumulation mitigates ischemic demyelination and cognitive function through stabilizing paranodal structure.
Fig. 4: Alleviating mitochondrial excessive accumulation promotes paranodal stability.
Fig. 5: Oxidative modification of protein 4.1B by mitochondrial ROS impairs paranodes.
Fig. 6: Re-establishment of mitochondrial mobility stabilizes the myelin structure and neural function by reducing mitochondrial ROS production.

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Data availability

Data sets presented in this study are included in full whenever possible, including a display of individual data points. Data were available from the corresponding author upon reasonable request. The source data for all figures and supplementary figures are provided as a Source Data file. Supplementary information is available on MP’s website.

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Funding

This study was supported by the Ministry of Science and Technology of China (STI2030- Major Projects 2021ZD0201806 to M.C. and 2021YFC2500100 to Q.D), National Natural Science Foundation of China (82271221 to M.C.; 82071197 to Q.D.; 82101336 to M.G.; 82201468 to YW. F.; 82373658 to YF. J).

Author information

Author notes

  1. These authors contributed equally: Yiwei Feng, Min Guo, Tongyao You.

Authors and Affiliations

  1. Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China

    Yiwei Feng, Min Guo, Tongyao You, Sida Han & Hongchen Zhao

  2. Department of Neurology, The 10th People’s Hospital, Tongji University, Shanghai, China

    Minjie Zhang, Junchao Xie & Yanxin Zhao

  3. State Key Laboratory of Genetic Engineering, Human Phenome Institute, and School of Life Sciences, Fudan University, Shanghai, China

    Jincheng Li & Yanfeng Jiang

  4. Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China

    Jintai Yu, Qiang Dong & Mei Cui

Authors
  1. Yiwei Feng
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  2. Min Guo
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Contributions

Conceptualization, MC, QD, JY and YZ; formal analysis, YF; investigation, YF, MZ, JX, SH, JL and HZ; writing—original draft preparation, MG and TY; writing—review and editing, MG, TY, YZ, QD and MC; supervision, MC; funding acquisition, MG, QD, YJ and MC.

Corresponding authors

Correspondence to Yanxin Zhao, Jintai Yu, Qiang Dong or Mei Cui.

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Competing interests

The authors declare no competing interests.

Ethics approval

All procedures were performed following the Guide for the National Science Council of the People’s Republic of China, and the study was approved by the Ethics Committee of Fudan University, Shanghai, China (IRB approval number 20180972A259). This manuscript was written in accordance with the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines.

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Feng, Y., Guo, M., You, T. et al. Paranodal instability driven by axonal mitochondrial accumulation in ischemic demyelination and cognitive decline. Mol Psychiatry 30, 3502–3515 (2025). https://doi.org/10.1038/s41380-025-02936-y

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