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

Baige Cao¹, Lei Fang¹, Yinan Zhang², Chuwen Lin¹, Peng Liu³, Huina Zhang⁴, Orion Fan⁴, Ming Xu⁵, Zhao Qin⁶, Congrong Wang⁷

Affiliations

¹ Department of Endocrinology & Metabolism, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.
² The Metabolic Disease Biobank, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
³ 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.
⁴ Stem Cell Translational Research Center, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
⁵ Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China. Electronic address: mingxu@shsmu.edu.cn.
⁶ 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; Innovation Center of Medical Basic Research for Brain Aging and Associated Diseases, Ministry of Education, Tongji University, Shanghai 200331, China; Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200331, China. Electronic address: zqin.med@tongji.edu.cn.
⁷ Department of Endocrinology & Metabolism, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China. Electronic address: crwang@tongji.edu.cn.

PMID: 40850503
DOI: 10.1016/j.jgg.2025.08.007

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

Baige Cao et al. J Genet Genomics. 2025.

. 2025 Aug 22:S1673-8527(25)00229-2.

doi: 10.1016/j.jgg.2025.08.007. Online ahead of print.

Authors

Baige Cao¹, Lei Fang¹, Yinan Zhang², Chuwen Lin¹, Peng Liu³, Huina Zhang⁴, Orion Fan⁴, Ming Xu⁵, Zhao Qin⁶, Congrong Wang⁷

Affiliations

¹ Department of Endocrinology & Metabolism, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.
² The Metabolic Disease Biobank, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
³ 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.
⁴ Stem Cell Translational Research Center, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
⁵ Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China. Electronic address: mingxu@shsmu.edu.cn.
⁶ 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; Innovation Center of Medical Basic Research for Brain Aging and Associated Diseases, Ministry of Education, Tongji University, Shanghai 200331, China; Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200331, China. Electronic address: zqin.med@tongji.edu.cn.
⁷ Department of Endocrinology & Metabolism, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China. Electronic address: crwang@tongji.edu.cn.

PMID: 40850503
DOI: 10.1016/j.jgg.2025.08.007

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 gene (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.

Keywords: C. elegans; MitoQ; Mitochondrial quality control; USCs; m.3243A>G.

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Conflict of interest The authors declare no competing financial interests.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources

Research Materials