Mitochondrial dysfunction promotes the necroptosis of Purkinje cells in the cerebellum of acrylamide-exposed rats

Huang, Zhaoqin; Wang, Shuai; Yang, Yiyu; Lou, Jian-Wei; Liu, Zhaoxiong; Liu, Zhidan; Yong, Hui; Shan, Shulin; Song, Fuyong

doi:10.1016/j.fct.2022.113522

Cited by 14 publications

(10 citation statements)

References 54 publications

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“…At the same time, RAPA is reported to inhibit the accumulation of p-RIPK1 and p-MLKL (Huang et al, 2023). Intervention with RAPA would enhance mitophagic flux to timely clear damaged mitochondria and inhibits ACR-induced programmed necrosis and further SARM1-related nerve damage.…”

Section: Discussionmentioning

confidence: 96%

“…The intervention with RAPA inhibits the up‐regulation of SARM1 in the spinal cord, delaying symptoms of neurobehavioral abnormalities in rats. At the same time, RAPA is reported to inhibit the accumulation of p‐RIPK1 and p‐MLKL (Huang et al, 2023). Intervention with RAPA would enhance mitophagic flux to timely clear damaged mitochondria and inhibits ACR‐induced programmed necrosis and further SARM1‐related nerve damage.…”

Section: Discussionmentioning

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: 96%

Section: Discussionmentioning

confidence: 99%

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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“…This indicated that mitochondrial fission was significantly active in URSA. Moreover, given that mitochondrial fission is increased in URSA, and that mitochondrial fission is closely related to necroptosis (21)(22)(23), we further explored the effect of mitochondrial fission on necroptosis and decidualization in vitro. First, TA9 was applied to successfully induce mitochondrial fission, characterized by the increased expression of (western blot: Drp1 P<0.05; Fis1 P<0.01. immunofluorescence: Drp1 and Fis1 P<0.05) (Figure 4A-D).…”

Section: Mitochondrial Fission Was Significantly Active In Ursamentioning

confidence: 99%

Baicalin Ameliorates Defective Decidualization in URSA by Regulating Mitochondrial Fission Induced Necroptosis

Zhao

Yang

et al. 2023

Preprint

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Defective decidualization is a significant pathological feature of URSA. And the potential relationship between mitochondrial fission, necroptosis and defective decidualization remains unknown. Baicalin plays an important role in regulating mitochondrial fission and programmed cell death. However, whether baicalin has a protective effect on defective decidualization in URSA has not been reported thus far. This study aims to explore the mechanisms of mitochondrial fission induced necroptosis in defective decidualization in URSA and the regulation of baicalin. First, decidual tissues were collected from URSA and health controls. And then, T-hESC was treated with lipopolysaccharide (LPS), Tyrphostin A9 (TA9), TA9+necrostatin-1(Nec-1) and TA9+baicalin during in vitro decidualization. Besides, URSA mice were established and randomly administrated with low, medium, and high doses of baicalin as well as saline. Results showed that decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein-1 (IGFBP1) in patients with URSA were significantly decreased (P<0.05). The incidence of cell necroptosis was increased, manifested with increased Annexin V and PI positive cells, high level of pRIP3 T231(P<0.01) and pMLKL S358 (P<0.05). Moreover, mitochondrial fission was also hyperactive, featured by elevated level of Fis1 (P<0.01) and Drp1 (P<0.05). In vitro experiments, LPS was induced to trigger necroptosis of T-hESC during induced decidualization, and IGFBP1 and PRL were subsequently decreased (P<0.05). Besides, mitochondrial fission inducer TA9 promoted the level of necroptosis (P<0.05) and induced defective decidualization, which could be rescued by necroptosis inhibitor Nec-1 (P<0.05). In addition, baicalin could reduce mitochondrial fission (P<0.05), necroptosis (P<0.05) and ameliorate defective decidualization in vivo and in vitro (P<0.05). In conclusion, hyperactive mitochondrial fission could promote necroptosis, thus inducing defective decidualization. And baicalin could ameliorates defective decidualization in URSA by regulating mitochondrial fission induced necroptosis.

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“…SARM1 accumulates on mitochondrial outer membrane during acrylamide intoxication (Shuai Wang et al., 2022). Moreover, treatment with the autophagy modulator rapamycin improves mitochondrial abnormalities and alleviates acrylamide‐induced axon degeneration (Huang et al., 2023; Wang et al., 2022).…”

Section: Figurementioning

confidence: 99%

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 dysfunction promotes the necroptosis of Purkinje cells in the cerebellum of acrylamide-exposed rats

Cited by 14 publications

References 54 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

Baicalin Ameliorates Defective Decidualization in URSA by Regulating Mitochondrial Fission Induced Necroptosis

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

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