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ORIGINAL RESEARCH article

Front. Aging Neurosci.

Sec. Parkinson’s Disease and Aging-related Movement Disorders

Volume 17 - 2025 | doi: 10.3389/fnagi.2025.1611958

MFN2-A Multifaceted Guardian Against Parkinson's Pathophysiology: Mitochondria, Ferroptosis, Inflammation and Oxidative Stress

Provisionally accepted
Yan  ChengYan Cheng1Hongjiang  ZhaiHongjiang Zhai1*Yong  LiuYong Liu1Yun-Zhou  YangYun-Zhou Yang1Bo  FangBo Fang1Mingxiang  SongMingxiang Song1Xiuqin  WangXiuqin Wang1Ping  ZhongPing Zhong2*
  • 1Lu'an hospital of Anhui medical university, Lu'an, China
  • 2Suzhou Hospital of Anhui Medical University, Suzhou, China

The final, formatted version of the article will be published soon.

Background: Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide and its exact pathogenesis remains unclear. This study aims to comprehensively explore the role of MFN2 in PD based on in vivo and in vitro models for multidimensional understanding. Methods: In vivo, C57BL/6J male mice were administered MPTP and probenecid by intraperitoneal injection to establish PD models. Lentivirus carrying MFN2 was microinjected into the bilateral striatum of specific groups of mice. The motor and cognitive functions of the mice were evaluated using the rotarod test and the open field test. In vitro, SH-SY5Y cells were treated with MPP⁺ to establish cell-based PD models. Transfection of plasmids was used to achieve overexpression or knockdown of MFN2. Subsequently, a series of experiments such as qRT-PCR, Western blot, CCK-8, flow cytometry and ELISA were used to verify the potential mechanism of MFN2. Results: In PD models, the expressions of DHODH, MFN1, MFN2, GPX4, and FSP1 were significantly down-regulated, and their motor coordination, self-cognitive behavior, and exploration ability were decreased. Concurrently, inflammatory and oxidative stress responses were enhanced, cell viability was weakened, apoptosis was increased, and mitochondrial abnormalities were observed. Overexpression of MFN2 improved the motor, cognitive and neurological damage in mice, enhanced cell viability, inhibited apoptosis, reduced the levels of inflammatory and oxidative stress factors, and up-regulated the expressions of DHODH, MFN1, GPX4 and FSP1. Mitochondrial morphological observation showed that MFN2 overexpression alleviated mitochondrial abnormalities. Conclusion: MFN2 may play a protective role in PD by regulating mitochondrial function, ferroptosis, inflammation and oxidative stress-related factors, providing a new theoretical basis and potential therapeutic targets for the treatment of PD.

Keywords: Parkinson's disease, Mitofusin 2, ferroptosis, Inflammatory, Oxidative Stress, Mitochondrial function

Received: 15 Apr 2025; Accepted: 01 Sep 2025.

Copyright: © 2025 Cheng, Zhai, Liu, Yang, Fang, Song, Wang and Zhong. 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:
Hongjiang Zhai, Lu'an hospital of Anhui medical university, Lu'an, China
Ping Zhong, Suzhou Hospital of Anhui Medical University, Suzhou, China

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