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

Wang, Shuai; Song, Mingxue; Yong, Hui; Zhang, Cuiqin; Kang, Kang; Liu, Zhidan; Yang, Yiyu; Huang, Zhaoqin; Wang, Shue; Ge, Haotong; Zhao, Xianxian; Song, Fuyong

doi:10.1007/s12035-022-03050-8

Cited by 7 publications

(10 citation statements)

References 70 publications

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“…And there is increasing evidence indicating that RAPA could regulate mitochondrial function via modulating mitophagy (Lenzi et al, 2021; Oaks et al, 2016; Pan et al, 2009; Shen et al, 2018), which may represent a useful therapeutic strategy in a variety of neurological diseases (Li et al, 2018; Wang, Fu, et al, 2021). Our recently published manuscript also demonstrates the inhibition of RAPA on ACR neurotoxicity (Wang, Song, et al, 2022). The intervention with RAPA inhibits the up‐regulation of SARM1 in the spinal cord, delaying symptoms of neurobehavioral abnormalities in rats.…”

Section: Discussionmentioning

confidence: 63%

“…However, there is evidence that ACR inhibits the lysosomal degradation of the autophagosome (Deng et al, 2022; Song et al, 2021). Through live‐cell imaging and western blotting of lysosomal hydrolases, we discover that lysosomal hyperplasia is inducted by ACR in our previous study (Wang, Song, et al, 2022). We speculate that this difference may be related to ACR dose, treatment time, and cell type.…”

Section: Discussionmentioning

confidence: 68%

“…We also tested necroptosis‐related molecules in the RAPA intervention model, a model that has been validated to reduce the SARM1 expression and to inhibit ACR‐caused axonal destruction (Wang, Song, et al, 2022). The pulsatile enhancement of basal autophagic flux mitigated the activation of the non‐canonical necroptotic pathways (Figure 8a).…”

Section: Resultsmentioning

confidence: 99%

“…The relevant multi‐omics data indicate that the nicotinamide adenine dinucleotide (NAD+) level, the key maintainer of low SARM1 activity in health axons (Di Stefano et al, 2015; Essuman et al, 2017; Figley et al, 2021; Gerdts et al, 2015), is still maintained at a relatively high level in the ACR intoxication model (Prats et al, 2017), instead of being depleted by SARM1. The NAD+ synthetase, nicotinamide mononucleotide adenylyltransferase 2, is also detected not to be reduced in ACR‐intoxicated rats (Wang, Song, et al, 2022). In addition, only early, non‐specific changes (cytoplasmic hyperchromatic motor neurons, for instance) were observed here.…”

Section: Discussionmentioning

confidence: 99%

“…What's more, SARM1 has an evolutionarily conserved mitochondrial targeting sequence (Panneerselvam et al, 2012) and could induce mitophagy by binding to and stabilizing PTEN‐induced putative kinase 1 (PINK1), a key molecule in the selective clearance of impaired mitochondria (Murata et al, 2013). Our previous studies indicate that ACR up‐regulates SARM1, and the overexpressed SARM1 accumulates on the outer mitochondrial membrane and interferes with mitochondrial dynamics (Wang, Song, et al, 2022; Wang, Zhang, et al, 2022). This axon destruction‐associated molecule, SARM1, is enriched in the axon and subsequently overexpressed in the neuron soma with increased doses, consistent with the dying‐back pathological process of ACR neuropathy that starts from axons and escalates to somas and providing a new idea for exploring the mechanism of ACR neurotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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Mitophagy suppresses motor neuron necroptotic mitochondrial damage and alleviates necroptosis that converges to SARM1 in acrylamide‐induced dying‐back neuropathy

Wang

Yang

et al. 2023

Journal of Neurochemistry

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Acrylamide (ACR), a common industrial ingredient that is also found in many foodstuffs, induces dying-back neuropathy in humans and animals. However, the mechanisms remain poorly understood. Sterile alpha and toll/interleukin 1 receptor motif-containing protein 1 (SARM1) is the central determinant of axonal degeneration and has crosstalk with different cell death programs to determine neuronal survival. Herein, we illustrated the role of SARM1 in ACR-induced dying-back neuropathy. We further demonstrated the upstream programmed cell death mechanism of this SARM1-dependent process. Spinal cord motor neurons that were induced to overexpress SARM1 underwent necroptosis rather than apoptosis in ACR neuropathy. Mechanically, noncanonical necroptotic pathways mediated mitochondrial permeability transition pore (mPTP) opening, reactive oxygen species (ROS) production, and mitochondrial fission.What's more, the final executioner of necroptosis, phosphorylation-activated mixed lineage kinase domain-like protein (MLKL), aggregated in mitochondrial fractions.Rapamycin intervention removed the impaired mitochondria, inhibited necroptosis for axon maintenance and neuronal survival, and alleviated ACR neuropathy. Our work clarified the functional links among mitophagy, necroptosis, and SARM1-dependent axonal destruction during ACR intoxication, providing novel therapeutic targets for dying-back neuropathies.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mitophagy suppresses motor neuron necroptotic mitochondrial damage and alleviates necroptosis that converges to SARM1 in acrylamide‐induced dying‐back neuropathy

Wang

Yang

et al. 2023

Journal of Neurochemistry

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Deregulated mitochondrial quality control, the heel of Achilles in elucidating the role of autophagy in SARM1‐mediated axon degeneration

Wang,

Zhang,

Song

et al. 2023

J of Neuroscience Research

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Autophagic dysfunction in neurodegenerative diseases is being extensively studied, yet the exact mechanism of macroautophagy/autophagy in axon degeneration is still elusive. A recent study by Kim et al. links autophagic stress to the sterile α and toll/interleukin 1 receptor motif containing protein 1 (SARM1)‐dependent core axonal degeneration program, providing a new insight into the role of autophagy in axon degeneration. In the classical Wallerian axon degeneration model of axotomy, disruption of axonal transport destroys the coordinated activity of pro‐survival and pro‐degenerative factors in the axoplasm and activates the NADase activity of SARM1, thus triggering the axonal self‐destruction program. However, the mechanism for SARM1 activation in the chronic neurodegenerative disorders is more complex. Mitochondrial defects and oxidative stress contribute to the activation of SARM1, while mitophagy can inhibit mitochondrial dysfunction and promote the clearance of SARM1 on mitochondria, thus protecting against neuronal degeneration. Therefore, in‐depth elucidation of the underlying mechanisms of mitophagy during axonal degeneration can help develop promising strategies for the prevention and treatment of various neurodegenerative disorders.

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Mitochondrial oxidative stress regulates LonP1-TDP-43 pathway and rises mitochondrial damage in carbon tetrachloride-induced liver fibrosis

Shan,

Liu,

Wang

et al. 2023

Ecotoxicology and Environmental Safety

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

Cited by 7 publications

References 70 publications

Mitophagy suppresses motor neuron necroptotic mitochondrial damage and alleviates necroptosis that converges to SARM1 in acrylamide‐induced dying‐back neuropathy

Mitophagy suppresses motor neuron necroptotic mitochondrial damage and alleviates necroptosis that converges to SARM1 in acrylamide‐induced dying‐back neuropathy

Deregulated mitochondrial quality control, the heel of Achilles in elucidating the role of autophagy in SARM1‐mediated axon degeneration

Mitochondrial oxidative stress regulates LonP1-TDP-43 pathway and rises mitochondrial damage in carbon tetrachloride-induced liver fibrosis

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