Sex-specific role of sensory neuron LKB1 on metabolic stress-induced mechanical hypersensitivity and mitochondrial respiration.
Sex-specific role of sensory neuron LKB1 on metabolic stress-induced mechanical hypersensitivity and mitochondrial respiration.
复制标题
感觉神经元 LKB1 对代谢应激诱导的机械超敏反应和线粒体呼吸的性别特异性作用。
DOI：
10.1152/ajpregu.00279.2021
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Burton,MichaelD
中科院分区：
文献类型：
--
作者：
Garner,KatherineM;Burton,MichaelD
疼痛障碍通过减少线粒体输出、改变细胞代谢和改变能量使用，诱导外周感觉神经元代谢应激。这些过程暗示神经元代谢是创造新疗法的途径。肝激酶B1 （LKB1）通过诱导5 ' -腺苷单磷酸活化激酶（AMPK）通路介导细胞对代谢应激的反应。LKB1-AMPK通路增加能量产生过程，包括线粒体输出。这些过程通过直接或间接地恢复细胞内的能量平衡来抑制疼痛。尽管LKB1-AMPK通路与疼痛缓解有关，但目前尚不清楚哪个细胞负责这一特性，以及与细胞代谢的直接联系。为了阐明这一点，我们建立了一个遗传小鼠模型，其中LKB1选择性地从Nav1.8+疼痛感觉神经元中去除，并通过禁食24小时对其进行代谢应激。我们发现雌性（而不是雄性）具有神经元特异性的、LKB1依赖性的代谢应激诱导的线粒体代谢恢复。这反映在机械过敏中，LKB1的缺失导致雌性动物过敏，而雄性动物没有。这种差异表明性别和细胞特异性对lkb1依赖性禁食诱导的机械超敏反应有贡献。尽管我们的数据表明LKB1以代谢特异性方式在抗疼痛途径中发挥潜在作用，但必须做更多的工作来研究这些性别差异。
Pain disorders induce metabolic stress in peripheral sensory neurons by reducing mitochondrial output, shifting cellular metabolism, and altering energy use. These processes implicate neuronal metabolism as an avenue for creating novel therapeutics. Liver kinase B1 (LKB1) mediates the cellular response to metabolic stress by inducing the 5′-adenosine monophosphate activated kinase (AMPK) pathway. The LKB1-AMPK pathway increases energy-producing processes, including mitochondrial output. These processes inhibit pain by directly or indirectly restoring energetic balance within a cell. Although the LKB1-AMPK pathway has been linked to pain relief, it is not yet known which cell is responsible for this property, as well any direct ties to cellular metabolism. To elucidate this, we developed a genetic mouse model where LKB1 is selectively removed from Nav1.8+ pain sensory neurons and metabolically stressed them by fasting for 24 h. We found females, but not males, had neuron-specific, LKB1-dependent restoration of metabolic stress-induced mitochondrial metabolism. This was reflected in mechanical hypersensitivity, where the absence of LKB1 led to hypersensitivity in female, but not male, animals. This discrepancy suggests a sex- and cell-specific contribution to LKB1-dependent fasting-induced mechanical hypersensitivity. Although our data represent a potential role for LKB1 in anti-pain pathways in a metabolic-specific manner, more must be done to investigate these sex differences.