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Mitochondrial Localization of SARM1 in Acrylamide Intoxication Induces Mitophagy and Limits Neuropathy

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Abstract

Sterile α and toll/interleukin 1 receptor motif-containing protein 1 (SARM1) is the defining molecule and central executioner of programmed axon death, also known as Wallerian degeneration. SARM1 has a mitochondrial targeting sequence, and it can bind to and stabilize PTEN-induced putative kinase 1 (PINK1) for mitophagy induction, but the deletion of the mitochondrial localization sequence is found to disrupt the mitochondrial localization of SARM1 in neurons without altering its ability to promote axon degeneration after axotomy. The biological significance of SARM1 mitochondrial localization remains elusive. In this study, we observed that the pro-degeneration factor, SARM1, was upregulated in acrylamide (ACR) neuropathy, a slow, Wallerian-like, programmed axonal death process. The upregulated SARM1 accumulated on mitochondria, interfered with mitochondrial dynamics, and activated PINK1-mediated mitophagy. Importantly, rapamycin (RAPA) intervention eliminated mitochondrial accumulation of SARM1 and partly attenuated ACR neuropathy. Thus, mitochondrial localization of SARM1 may contribute to its clearance through the SARM1-PINK1 mitophagy pathway, which inhibits axonal degeneration through a negative feedback loop. The mitochondrial localization of SARM1 complements the coordinated activity of the pro-survival factor, nicotinamide mononucleotide adenyltransferase 2 (NMNAT2), and SARM1 and is part of the self-limiting molecular mechanisms underpinning programmed axon death in ACR neuropathy.

Graphical abstract

Mitophagy clearance of SARM1 is complementary to the coordinated activity of NMNAT2 and SARM1 in ACR neuropathy.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ACR :

Acrylamide

ARM :

Armadillo repeats

cADPR :

Cyclic adenosine diphosphate ribose

NAD +  :

Nicotinamide adenine dinucleotide

NMN :

Nicotinamide mononucleotide

NMNAT2 :

Nicotinamide mononucleotide adenyltransferase 2

PINK1 :

PTEN-induced putative kinase 1

RAPA :

Rapamycin

SAM :

Sterile α motif

SARM :

Sterile α and toll/interleukin 1 receptor motif-containing protein 1

TIR :

Toll/interleukin 1 receptor

TRAF6 :

Tumor necrosis factor receptor-associated factor 6

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Acknowledgements

The authors want to thank the Translational Medicine Core Facility of Shandong University for consultation and instrument availability that supported this work, Editage (www.editage.cn) for English language editing, Lihua Yu and Wenwen Zheng for their assistance in experiments, and Wenhao Yu and Ziqiang Yu for their generous help in data analysis.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82173552; No. 81673209).

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Authors and Affiliations

  1. Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China

    Shuai Wang, Mingxue Song, Hui Yong, Cuiqin Zhang, Kang Kang, Zhidan Liu, Yiyu Yang, Zhengcheng Huang, Xiulan Zhao & Fuyong Song

  2. School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China

    Cuiqin Zhang, Shu’e Wang, Haotong Ge & Xiulan Zhao

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  10. Haotong Ge
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  11. Xiulan Zhao
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Contributions

Shuai Wang, a major contributor in writing the manuscript, performed the examination and analyzed and interpreted the data. Mingxue Song, Hui Yong, Cuiqin Zhang, Kang Kang, Zhidan Liu, Yiyu Yang, Zhengcheng Huang, Shu’e Wang Haotong Ge, and Xiulan Zhao contributed to the acquisition of data. Fuyong Song was responsible for the conception and design of the work. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Fuyong Song.

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Animals were treated according to the NIH Guide for Care and Use of Laboratory Animals and followed the principles in the “Use of Animals in Toxicology.” All protocols were approved by the Institutional Animal Care and Use Committee of Shandong University.

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Highlights

• The pro-degeneration factor, SARM1, is upregulated in ACR neuropathy.

• The upregulated SARM1 accumulates on mitochondria during ACR neuropathy.

• ACR induces mitophagy, and the SARM1-PINK1 pathway is one of the underlying molecular mechanisms.

• RAPA intervention clears mitochondrial SARM1 and partly attenuates ACR neuropathy.

• Mitophagy clearance of SARM1 complements the coordinated activity of NMNAT2 and SARM1.

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Wang, S., Song, M., Yong, H. et al. Mitochondrial Localization of SARM1 in Acrylamide Intoxication Induces Mitophagy and Limits Neuropathy. Mol Neurobiol 59, 7337–7353 (2022). https://doi.org/10.1007/s12035-022-03050-8

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  • DOI: https://doi.org/10.1007/s12035-022-03050-8

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