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

被引：7

作者：

Wang, Shuai ^{[1
]}

Yang, Yiyu ^{[1
]}

Yu, Zhigang ^{[2
]}

Song, Mingxue ^{[1
]}

Liu, Zhidan ^{[1
]}

Shan, Shulin ^{[1
]}

Yong, Hui ^{[1
]}

Ni, Wenting ^{[1
]}

Qiang, Yalong ^{[1
]}

Zhang, Cuiqin ^{[1
]}

Wang, Shu'e ^{[1
]}

Zhao, Xiulan ^{[1
]}

Song, Fuyong ^{[1
]}

机构：

[1] Shandong Univ, Cheeloo Coll Med, Sch Publ Hlth, Dept Toxicol & Nutr, 44 West Wenhua Rd, Jinan, Shandong, Peoples R China

[2] Jinan Municipal Ctr Dis Control & Prevent, Inst Phys & Chem Anal, Jinan, Shandong, Peoples R China

来源：

JOURNAL OF NEUROCHEMISTRY | 2023年 / 166卷 / 03期

基金：

中国国家自然科学基金;

关键词：

acrylamide; axonal necroptosis; dying-back neuropathy; mitophagy; neurodegeneration; SARM1; SPINAL-CORD-INJURY; PERIPHERAL NEUROPATHY; INTERACTING PROTEIN; OXIDATIVE STRESS; CELL-DEATH; RAT MODEL; PGAM5; DEGENERATION; ACTIVATION; RAPAMYCIN;

D O I：

10.1111/jnc.15889

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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, non-canonical 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.

引用

页码：588 / 608

页数：21