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The Mitochondrial-Derived Peptide (MOTS-c) Interacted with Nrf2 to Defend the Antioxidant System to Protect Dopaminergic Neurons Against Rotenone Exposure

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Abstract

MOTS-c is a 16-amino acid mitochondrial-derived peptide reported to be involved in regulating energy metabolism. However, few studies have reported the role of MOTS-c on neuron degeneration. In this study, it was aimed to explore the action of MOTS-c in rotenone-induced dopaminergic neurotoxicity. In an in vitro study, it was observed that rotenone could influence the expression and localization of MOTS-c significantly in PC12 cells, with more MOTS-c translocating into the nucleus from mitochondria. Further study showed that the translocation of MOTS-c from the mitochondria into the nucleus could directly interact with Nrf2 to regulate HO-1 and NQO1 expression in PC12 cells exposed to rotenone, which had been suggested to be involved in the antioxidant defense system. In vivo and in vitro experiments demonstrated that exogenous MOTS-c pretreatment could protect PC12 cells and rats from mitochondrial dysfunction and oxidative stress induced by rotenone. Moreover, MOTS-c pretreatment significantly decreased the loss of TH, PSD95, and SYP protein expression in the striatum of rats exposed to rotenone. In addition, MOTS-c pretreatment could clearly alleviate the downregulated expression of Nrf2, HO-1, and NQO1, as well as the upregulated Keap1 protein expression in the striatum of rotenone-treated rats. Taken together, these findings suggested that MOTS-c could directly interact with Nrf2 to activate the Nrf2/HO-1/NQO1 signal pathway to defend the antioxidant system to prevent dopaminergic neurons from rotenone-induced oxidative stress and neurotoxicity in vitro and in vivo.

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Data Availability

All data that support the findings of this study are available from the corresponding author upon request.

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Funding

This work was supported by grants from the NSFC (Natural Science Foundation of China) (81973090) to Yan Sai.

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Author notes

  1. Jingsong Xiao, Qifu Zhang and Yaohui Shan contributed equally to this work.

Authors and Affiliations

  1. Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China

    Jingsong Xiao, Qifu Zhang, Yaohui Shan, Feng Ye, Xi Zhang, Jin Cheng, Xiaogang Wang, Yuanpeng Zhao, Guorong Dan, Mingliang Chen & Yan Sai

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  1. Jingsong Xiao
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Contributions

JX contributed to investigation, writing—original draft, and visualization; QF and YH were involved in investigation; FY, XZ, JC, GD, XG, and YZ made software; ML contributed to writing—review and editing; YS performed project administration, conceptualization, supervision, validation, and writing—review and editing.

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Correspondence to Yan Sai.

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Animal care and all experimental procedures were conducted in compliance with the Animal Ethics Committee of the Third Military Medical University. All efforts were made to minimize the number of animals used and their suffering. All experimental procedures were approved by the Ethics Committee of Third Military Medical University. The animal use was conducted in accordance with the National Institutes of Health guidelines for the Care and Use of Laboratory Animals and by the Animal Ethics Committee of Third Military Medical University.

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Xiao, J., Zhang, Q., Shan, Y. et al. The Mitochondrial-Derived Peptide (MOTS-c) Interacted with Nrf2 to Defend the Antioxidant System to Protect Dopaminergic Neurons Against Rotenone Exposure. Mol Neurobiol 60, 5915–5930 (2023). https://doi.org/10.1007/s12035-023-03443-3

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