MitoQ alleviates m.3243A&gt;G-induced mitochondrial dysfunction by stabilizing PINK1 and enhancing mitophagy

Baige Cao; Lei Fang; Yinan Zhang; Chuwen Lin; Peng Liu; Huina Zhang; Orion Fan; Ming Xu; Zhao Qin; Congrong Wang

doi:10.1016/j.jgg.2025.08.007

MitoQ alleviates m.3243A>G-induced mitochondrial dysfunction by stabilizing PINK1 and enhancing mitophagy

doi: 10.1016/j.jgg.2025.08.007

a. Department of Endocrinology & Metabolism, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China;
b. The Metabolic Disease Biobank, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China;
c. Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China;
d. Stem Cell Translational Research Center, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China;
e. Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China;
f. Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China;
g. Innovation Center of Medical Basic Research for Brain Aging and Associated Diseases, Ministry of Education, Tongji University, Shanghai 200331, China;
h. Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200331, China

基金项目:

We thank Yiquan Tang, Haijun Tu, and Shangbang Gao for reagents. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This work was supported by the National Natural Science Foundation of China (Grant No. 82471893 and 82070913), Key discipline project of Hongkou District Health Commission (HKLCFC202403), Tongji Hospital Start-up Funding for Scientific Research (RCQD2301) and Research fund from Shanghai Fourth People’s Hospital (sykyqd01801, SY-XKZT-2021-1001).

详细信息

通讯作者:
Ming Xu,E-mail:mingxu@shsmu.edu.cn

Zhao Qin,E-mail:zqin.med@tongji.edu.cn

Congrong Wang,E-mail:crwang@tongji.edu.cn

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出版历程
- 收稿日期: 2025-04-07
- 录用日期: 2025-08-15
- 修回日期: 2025-08-11
- 网络出版日期: 2025-08-26

MitoQ alleviates m.3243A>G-induced mitochondrial dysfunction by stabilizing PINK1 and enhancing mitophagy

Baige Cao^a,
Lei Fang^a,
Yinan Zhang^b,
Chuwen Lin^a,
Peng Liu^c,
Huina Zhang^d,
Orion Fan^d,
Ming Xu^{e
, ,},
Zhao Qin^{f,g,h
, ,},
Congrong Wang^{a
, ,}

a. Department of Endocrinology & Metabolism, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China;
b. The Metabolic Disease Biobank, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China;
c. Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China;
d. Stem Cell Translational Research Center, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China;
e. Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China;
f. Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China;
g. Innovation Center of Medical Basic Research for Brain Aging and Associated Diseases, Ministry of Education, Tongji University, Shanghai 200331, China;
h. Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200331, China

Funds:

摘要

摘要: The mitochondrial 3243A>G mutation (m.3243A>G) is associated with diverse clinical phenotypes. To elucidate the underlying mechanisms and explore intervention strategies in m.3243A>G patients, urine-derived stem cells (USCs) and a mitochondrial leucyl-tRNA synthetase (lars-2) deficient Caenorhabditis elegans (C. elegans) model are used to assess mitochondrial homeostasis and neuromuscular dysfunction. Patient-derived USCs with high levels of m.3243A>G heteroplasmy exhibit impaired mitochondrial function, disrupted mitochondrial dynamics, and inhibited mitophagy, which are reversed by MitoQ through suppression of OMA1 zinc metallopeptidase (OMA1)-induced mitochondrial phosphatase and tensin (PTEN) induced kinase 1 (PINK1) degradation. Furthermore, lars-2 knockdown in C. elegans induces mitochondrial stress and mimics the loss of neural and muscle functions observed in patients with the m.3243A>G mutation. MitoQ treatment partially improves neurobehavioral function by promoting the PINK1 pathway. These findings suggest that MitoQ has therapeutic potential in the context of the m.3243A>G mutation.
- m.3243A> /
- G /
- USCs /
- Mitochondrial quality control /
- MitoQ /
- C. elegans
Abstract: The mitochondrial 3243A>G mutation (m.3243A>G) is associated with diverse clinical phenotypes. To elucidate the underlying mechanisms and explore intervention strategies in m.3243A>G patients, urine-derived stem cells (USCs) and a mitochondrial leucyl-tRNA synthetase (lars-2) deficient Caenorhabditis elegans (C. elegans) model are used to assess mitochondrial homeostasis and neuromuscular dysfunction. Patient-derived USCs with high levels of m.3243A>G heteroplasmy exhibit impaired mitochondrial function, disrupted mitochondrial dynamics, and inhibited mitophagy, which are reversed by MitoQ through suppression of OMA1 zinc metallopeptidase (OMA1)-induced mitochondrial phosphatase and tensin (PTEN) induced kinase 1 (PINK1) degradation. Furthermore, lars-2 knockdown in C. elegans induces mitochondrial stress and mimics the loss of neural and muscle functions observed in patients with the m.3243A>G mutation. MitoQ treatment partially improves neurobehavioral function by promoting the PINK1 pathway. These findings suggest that MitoQ has therapeutic potential in the context of the m.3243A>G mutation.
- m.3243A> /
- G /
- USCs /
- Mitochondrial quality control /
- MitoQ /
- C. elegans

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参考文献(32)

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MitoQ alleviates m.3243A>G-induced mitochondrial dysfunction by stabilizing PINK1 and enhancing mitophagy

doi: 10.1016/j.jgg.2025.08.007

通讯作者:
Ming Xu,E-mail:mingxu@shsmu.edu.cn

Zhao Qin,E-mail:zqin.med@tongji.edu.cn

Congrong Wang,E-mail:crwang@tongji.edu.cn

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MitoQ alleviates m.3243A>G-induced mitochondrial dysfunction by stabilizing PINK1 and enhancing mitophagy

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MitoQ alleviates m.3243A>G-induced mitochondrial dysfunction by stabilizing PINK1 and enhancing mitophagy

doi: 10.1016/j.jgg.2025.08.007

通讯作者: Ming Xu,E-mail:mingxu@shsmu.edu.cn Zhao Qin,E-mail:zqin.med@tongji.edu.cn Congrong Wang,E-mail:crwang@tongji.edu.cn

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MitoQ alleviates m.3243A>G-induced mitochondrial dysfunction by stabilizing PINK1 and enhancing mitophagy

计量

出版历程

目录

通讯作者:
Ming Xu,E-mail:mingxu@shsmu.edu.cn

Zhao Qin,E-mail:zqin.med@tongji.edu.cn

Congrong Wang,E-mail:crwang@tongji.edu.cn