Abstract：
UNASSIGNED: Metabolism is inextricably linked to every aspect of cellular function. In addition to energy production and biosynthesis, metabolism plays a crucial role in regulating signal transduction and gene expression. Altered metabolic states have been shown to maintain aberrant signaling and transcription, contributing to diseases like cancer, cardiovascular disease, and neurodegeneration. Metabolic gene polymorphisms and defects are also associated with chronic pain conditions, as are increased levels of nerve growth factor (NGF). However, the mechanisms by which NGF may modulate sensory neuron metabolism remain unclear. This study demonstrated that intraplantar NGF injection reprograms sensory neuron metabolism. Nerve growth factor suppressed mitochondrial pyruvate oxidation and enhanced lactate extrusion, requiring 24 hours to increase lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 (PDHK1) expression. Inhibiting these metabolic enzymes reversed NGF-mediated effects. Remarkably, directly disrupting mitochondrial pyruvate oxidation induced severe, persistent allodynia, implicating this metabolic dysfunction in chronic pain. Nanopore long-read sequencing of poly(A) mRNA uncovered extensive transcriptomic changes upon metabolic disruption, including altered gene expression, splicing, and poly(A) tail lengths. By linking metabolic disturbance of dorsal root ganglia to transcriptome reprogramming, this study enhances our understanding of the mechanisms underlying persistent nociceptive sensitization. These findings imply that impaired mitochondrial pyruvate oxidation may drive chronic pain, possibly by impacting transcriptomic regulation. Exploring these metabolite-driven mechanisms further might reveal novel therapeutic targets for intractable pain.
摘要：
■代谢与细胞功能的各个方面密不可分。除了能源生产和生物合成，代谢在调节信号传导和基因表达中起着至关重要的作用。已显示改变的代谢状态维持异常的信号传导和转录，导致癌症等疾病，心血管疾病,和神经变性。代谢基因多态性和缺陷也与慢性疼痛有关。神经生长因子（NGF）水平升高。然而,NGF调节感觉神经元代谢的机制尚不清楚.这项研究表明，足底内注射NGF会重新编程感觉神经元代谢。神经生长因子抑制线粒体丙酮酸氧化并增强乳酸挤压，需要24小时来增加乳酸脱氢酶A和丙酮酸脱氢酶激酶1（PDHK1）的表达。抑制这些代谢酶逆转了NGF介导的作用。值得注意的是,直接破坏线粒体丙酮酸氧化诱导严重，持续性异常性疼痛,这种代谢功能障碍与慢性疼痛有关。poly（A）mRNA的纳米孔长读数测序揭示了代谢破坏后广泛的转录组变化，包括改变的基因表达，拼接,和聚（A）尾部长度。通过将背根神经节的代谢紊乱与转录组重编程联系起来，本研究加深了我们对持续性伤害性敏感潜在机制的理解.这些发现暗示线粒体丙酮酸氧化受损可能导致慢性疼痛，可能通过影响转录组调节。探索这些代谢物驱动的机制可能进一步揭示顽固性疼痛的新治疗靶点。
