Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom
Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109.
J Neurosci. 2021 May 12;41(19):4321-4334. doi: 10.1523/JNEUROSCI.1852-20.2021. Epub 2021 Mar 30.
Peripheral neuropathy (PN) is the most common complication of prediabetes and diabetes. PN causes severe morbidity for Type 2 diabetes (T2D) and prediabetes patients, including limb pain followed by numbness resulting from peripheral nerve damage. PN in T2D and prediabetes is associated with dyslipidemia and elevated circulating lipids; however, the molecular mechanisms underlying PN development in prediabetes and T2D are unknown. Peripheral nerve sensory neurons rely on axonal mitochondria to provide energy for nerve impulse conduction under homeostatic conditions. Models of dyslipidemia demonstrate mitochondrial dysfunction in sensory neurons exposed to elevated levels of exogenous fatty acids. Herein, we evaluated the effect of dyslipidemia on mitochondrial function and dynamics in sensory axons of the saphenous nerve of a male high-fat diet (HFD)-fed murine model of prediabetes to identify mitochondrial alterations that correlate with PN pathogenesis We found that the HFD decreased mitochondrial membrane potential (MMP) in axonal mitochondria and reduced the ability of sensory neurons to conduct at physiological frequencies. Unlike mitochondria in control axons, which dissipated their MMP in response to increased impulse frequency (from 1 to 50 Hz), HFD mitochondria dissipated less MMP in response to axonal energy demand, suggesting a lack of reserve capacity. The HFD also decreased sensory axonal Ca levels and increased mitochondrial lengthening and expression of PGC1α, a master regulator of mitochondrial biogenesis. Together, these results suggest that mitochondrial dysfunction underlies an imbalance of axonal energy and Ca levels and impairs impulse conduction within the saphenous nerve in prediabetic PN. Diabetes and prediabetes are leading causes of peripheral neuropathy (PN) worldwide. PN has no cure, but development in diabetes and prediabetes is associated with dyslipidemia, including elevated levels of saturated fatty acids. Saturated fatty acids impair mitochondrial dynamics and function in cultured neurons, indicating a role for mitochondrial dysfunction in PN progression; however, the effect of elevated circulating fatty acids on the peripheral nervous system is unknown. In this study, we identify early pathogenic events in sensory nerve axons of mice with high-fat diet-induced PN, including alterations in mitochondrial function, axonal conduction, and intra-axonal calcium, that provide important insight into potential PN mechanisms associated with prediabetes and dyslipidemia .
周围神经病变 (PN) 是糖尿病前期和糖尿病最常见的并发症。PN 导致 2 型糖尿病 (T2D) 和糖尿病前期患者严重发病，包括肢体疼痛，随后因外周神经损伤导致麻木。T2D 和糖尿病前期的 PN 与血脂异常和循环脂质升高有关；然而，糖尿病前期和 T2D 中 PN 发展的分子机制尚不清楚。在稳态条件下，周围神经感觉神经元依赖轴突线粒体为神经冲动传导提供能量。血脂异常模型表明，暴露于高水平外源性脂肪酸的感觉神经元中线粒体功能障碍。在此，我们评估了血脂异常对雄性高脂肪饮食 (HFD) 喂养的糖尿病前期动物模型隐神经感觉轴突中线粒体功能和动力学的影响，以确定与 PN 发病机制相关的线粒体改变。我们发现，HFD 降低了轴突线粒体的线粒体膜电位 (MMP)，并降低了感觉神经元在生理频率下传导的能力。与对照轴突中的线粒体不同，对照轴突中的线粒体在响应增加的冲动频率（从 1 到 50 Hz）时会耗散其 MMP，而 HFD 线粒体在响应轴突能量需求时耗散的 MMP 较少，这表明储备能力不足。HFD 还降低了感觉轴突 Ca 水平，并增加了线粒体伸长和 PGC1α 的表达，PGC1α 是线粒体生物发生的主要调节因子。总之，这些结果表明，轴突能量和 Ca 水平的失衡以及隐神经中冲动传导的损害是糖尿病前期 PN 中线粒体功能障碍的基础。糖尿病前期和糖尿病是全球周围神经病变 (PN) 的主要原因。PN 无法治愈，但糖尿病前期和糖尿病的发展与血脂异常有关，包括饱和脂肪酸水平升高。饱和脂肪酸会损害培养神经元中线粒体的动态和功能，表明线粒体功能障碍在 PN 进展中的作用；然而，循环脂肪酸升高对周围神经系统的影响尚不清楚。在这项研究中，我们鉴定了高脂肪饮食诱导的 PN 小鼠感觉神经轴突中的早期致病事件，包括线粒体功能、轴突传导和轴内 Ca 的改变，这些改变为与糖尿病前期和血脂异常相关的潜在 PN 机制提供了重要的见解。
