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

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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

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:

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).

Received Date: 2025-04-07
Accepted Date: 2025-08-15
Rev Recd Date: 2025-08-11

Available Online: 2025-08-26

Abstract

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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References

Akabane, S., K. Watanabe, H. Kosako, S. I. Yamashita, K. Nishino, M. Kato, S. Sekine, T. Kanki, N. Matsuda, et al., 2023. TIM23 facilitates PINK1 activation by safeguarding against OMA1-mediated degradation in damaged mitochondria. Cell Rep. 42, 112454.

Benedetti, C., C. M. Haynes, Y. Yang, H. P. Harding and D. Ron, 2006. Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response. Genetics. 174, 229-239.

Bhattacharya, S., J. Yin, W. Huo and E. Chaum, 2022. Modeling of mitochondrial bioenergetics and autophagy impairment in MELAS-mutant iPSC-derived retinal pigment epithelial cells. Stem Cell Res. Ther. 13, 260.

Borner, G. V., M. Zeviani, V. Tiranti, F. Carrara, S. Hoffmann, K. D. Gerbitz, H. Lochmuller, D. Pongratz, T. Klopstock, et al., 2000. Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients. Hum. Mol. Genet. 9, 467-475.

Bowen, J., T. Richards and K. Maravilla, 1998. MR imaging and proton MR spectroscopy in A-to-G substitution at nucleotide position 3243 of leucine transfer RNA. AJNR Am. J. Neuroradiol. 19, 231-234.

Butterfield, D. A. and B. Halliwell, 2019. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat. Rev. Neurosci. 20, 148-160.

Chan, D. C., 2020. Mitochondrial dynamics and its involvement in disease. Annu. Rev. Pathol.: Pathol. Mech. Dis. 15, 235-259.

Cheng, W., Y. Zhang and L. He, 2022. MRI features of stroke-like episodes in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. Front. Neurol. 13, 843386.

Eldeeb, M. A., R. A. Thomas, M. A. Ragheb, A. Fallahi and E. A. Fon, 2022. Mitochondrial quality control in health and in Parkinson's disease. Physiol. Rev. 102, 1721-1755.

Elliott, H. R., D. C. Samuels, J. A. Eden, C. L. Relton and P. F. Chinnery, 2008. Pathogenic mitochondrial DNA mutations are common in the general population. Am. J. Hum. Genet. 83, 254-260.

Gao, X., Z. Jiang, X. Yan, J. Liu, F. Li, P. Liu, J. Li, Y. Wei, Y. E. Sun, et al., 2021. ATF5, a putative therapeutic target for the mitochondrial DNA 3243A>G mutation-related disease. Cell Death Dis. 12, 701.

Glenn, C. F., D. K. Chow, L. David, C. A. Cooke, M. S. Gami, W. B. Iser, K. B. Hanselman, I. G. Goldberg and C. A. Wolkow, 2004. Behavioral deficits during early stages of aging in Caenorhabditis elegans result from locomotory deficits possibly linked to muscle frailty. J. Gerontol. A Biol. Sci. Med. Sci. 59, 1251-1260.

Gorman, G. S., A. M. Schaefer, Y. Ng, N. Gomez, E. L. Blakely, C. L. Alston, C. Feeney, R. Horvath, P. Yu-Wai-Man, et al., 2015. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann. Neurol. 77, 753-759.

Hornig-Do, H. T., A. Montanari, A. Rozanska, H. A. Tuppen, A. A. Almalki, D. P. Abg-Kamaludin, L. Frontali, S. Francisci, R. N. Lightowlers, et al., 2014. Human mitochondrial leucyl tRNA synthetase can suppress non cognate pathogenic mt-tRNA mutations. EMBO Mol. Med. 6, 183-193.

Klein Gunnewiek, T. M., E. J. H. Van Hugte, M. Frega, G. S. Guardia, K. Foreman, D. Panneman, B. Mossink, K. Linda, J. M. Keller, et al., 2020. m.3243A>G-induced mitochondrial dysfunction impairs human neuronal development and reduces neuronal network activity and synchronicity. Cell Rep. 31, 107538.

Lee, S. S., R. Y. Lee, A. G. Fraser, R. S. Kamath, J. Ahringer and G. Ruvkun, 2003. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat. Genet. 33, 40-48.

Li, R. and M. X. Guan, 2010. Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial dysfunctions due to the tRNALeu(UUR) A3243G mutation, associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms and diabetes. Mol. Cell. Biol. 30, 2147-2154.

Madreiter-Sokolowski, C. T., A. A. Sokolowski, M. Waldeck-Weiermair, R. Malli and W. F. Graier, 2018. Targeting mitochondria to counteract age-related cellular dysfunction. Genes (Basel). 9.

Matsubara, M., H. Kanda, H. Imamura, M. Inoue, M. Noguchi, K. Hosoda, A. Kakizuka and K. Nakao, 2018. Analysis of mitochondrial function in human induced pluripotent stem cells from patients with mitochondrial diabetes due to the A3243G mutation. Sci. Rep. 8, 949.

Murphy, R., D. M. Turnbull, M. Walker and A. T. Hattersley, 2008. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet. Med. 25, 383-399.

Park, H., E. Davidson and M. P. King, 2003. The pathogenic A3243G mutation in human mitochondrial tRNALeu(UUR) decreases the efficiency of aminoacylation. Biochemistry. 42, 958-964.

Picard, M., J. Zhang, S. Hancock, O. Derbeneva, R. Golhar, P. Golik, S. O'Hearn, S. Levy, P. Potluri, et al., 2014. Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming. Proc. Natl. Acad. Sci. U.S.A. 111, E4033-4042.

Shirakabe, A., P. Zhai, Y. Ikeda, T. Saito, Y. Maejima, C. P. Hsu, M. Nomura, K. Egashira, B. Levine, et al., 2016. Drp1-dependent mitochondrial autophagy plays a protective role against pressure overload-induced mitochondrial dysfunction and heart failure. Circulation. 133, 1249-1263.

Su, L., J. Zhang, H. Gomez, J. A. Kellum and Z. Peng, 2023. Mitochondria ROS and mitophagy in acute kidney injury. Autophagy. 19, 401-414.

Suzuki, S., Y. Hinokio, M. Ohtomo, M. Hirai, A. Hirai, M. Chiba, S. Kasuga, Y. Satoh, H. Akai, et al., 1998. The effects of coenzyme Q10 treatment on maternally inherited diabetes mellitus and deafness, and mitochondrial DNA 3243 (A to G) mutation. Diabetologia. 41, 584-588.

Toth, M. L., I. Melentijevic, L. Shah, A. Bhatia, K. Lu, A. Talwar, H. Naji, C. Ibanez-Ventoso, P. Ghose, et al., 2012. Neurite sprouting and synapse deterioration in the aging Caenorhabditis elegans nervous system. J. Neurosci. 32, 8778-8790.

Twig, G. and O. S. Shirihai, 2011. The interplay between mitochondrial dynamics and mitophagy. Antioxid. Redox Signaling. 14, 1939-1951.

Wang, B., J. Nie, L. Wu, Y. Hu, Z. Wen, L. Dong, M. H. Zou, C. Chen and D. W. Wang, 2018. AMPKα2 protects against the development of heart failure by enhancing mitophagy via PINK1 phosphorylation. Circ. Res. 122, 712-729.

Xiao, L., X. Xu, F. Zhang, M. Wang, Y. Xu, D. Tang, J. Wang, Y. Qin, Y. Liu, et al., 2017. The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1. Redox Biol. 11, 297-311.

Yang, J., H. Suo and J. Song, 2021. Protective role of mitoquinone against impaired mitochondrial homeostasis in metabolic syndrome. Crit. Rev. Food Sci. Nutr. 61, 3857-3875.

Yokota, M., H. Hatakeyama, S. Okabe, Y. Ono and Y. Goto, 2015. Mitochondrial respiratory dysfunction caused by a heteroplasmic mitochondrial DNA mutation blocks cellular reprogramming. Hum. Mol. Genet. 24, 4698-4709.

Zhao, T., D. Luo, Y. Sun, X. Niu, Y. Wang, C. Wang and W. Jia, 2018. Human urine-derived stem cells play a novel role in the treatment of STZ-induced diabetic mice. J. Mol. Histol. 49, 419-428.

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