Mayorga-Weber Gonzalo, Alarcón Pablo, Peña-Münzenmayer Gaspar, Rojas Patricio, Burgos Rafael A, Rivera Francisco J, Castro Maite A
Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile.
Laboratory of Immunometabolism, Institute of Pharmacology and Morphophysiology, Faculty of Veterinary Sciences, Universidad Austral de Chile, Valdivia, Chile.
Free Radic Biol Med. 2025 Oct;238:417-429. doi: 10.1016/j.freeradbiomed.2025.06.044. Epub 2025 Jun 28.
The global population is aging, as reported by the World Health Organization (WHO). The brain, an energy-dependent organ, experiences a significant decline in energy production as we age. The corpus callosum, a major white matter tract, undergoes changes in energy metabolism during aging that remain poorly understood. This study aimed to investigate axonal energy metabolism in the corpus callosum and the potential role of Monocarboxylate Transporter 1 (MCT1) in age-related metabolic alterations. We analyzed the corpus callosum of young (3-4 months) and aged (18-24 months) mice, focusing on metabolic changes. Metabolomic analysis by gas chromatography-mass spectroscopy (GC-MS) revealed lactate accumulation, reduced glucose levels, and oxidative stress in the aged corpus callosum. Neuronal stimulation experiments using SoNar fluorescent sensor demonstrated a reduced capacity for oxidative energy metabolism in aged axons, evidenced by a lower axonal NADH/NAD + ratio during electrical stimulation. In young axons, oxidative energy metabolism is sustained by glycolysis, lactate production via lactate dehydrogenase (LDH), and lactate transport mediated by MCTs during electrical stimulation. However, these processes are significantly impaired in aged axons. Additionally, glucose oxidation shifted preferentially to the pentose phosphate pathway (PPP) during electrical stimulation, highlighting its role in mitigating oxidative stress in aging. We observed reduced lactate uptake and MCT1 expression in aging. This reduction likely disrupts lactate flux and oxidation, contributing to energy inefficiencies that may promote oxidative stress and axonal deterioration. Our findings emphasize the need for further investigation of the role of MCT1 and lactate metabolism as therapeutic targets to preserve white matter integrity and axonal function in the aging brain.
据世界卫生组织（WHO）报告，全球人口正在老龄化。大脑是一个能量依赖型器官，随着年龄的增长，其能量产生会显著下降。胼胝体是主要的白质束，在衰老过程中能量代谢会发生变化，而目前对此仍知之甚少。本研究旨在调查胼胝体中的轴突能量代谢以及单羧酸转运体1（MCT1）在与年龄相关的代谢改变中的潜在作用。我们分析了年轻（3 - 4个月）和老年（18 - 24个月）小鼠的胼胝体，重点关注代谢变化。通过气相色谱 - 质谱联用（GC - MS）进行的代谢组学分析显示，老年胼胝体中存在乳酸积累、葡萄糖水平降低和氧化应激。使用SoNar荧光传感器进行的神经元刺激实验表明，老年轴突中氧化能量代谢能力降低，电刺激期间轴突NADH/NAD + 比值降低证明了这一点。在年轻轴突中，电刺激期间氧化能量代谢通过糖酵解、经由乳酸脱氢酶（LDH）产生乳酸以及由MCTs介导的乳酸转运来维持。然而，这些过程在老年轴突中显著受损。此外，电刺激期间葡萄糖氧化优先转向磷酸戊糖途径（PPP），突出了其在减轻衰老过程中氧化应激方面的作用。我们观察到衰老过程中乳酸摄取和MCT1表达降低。这种降低可能会破坏乳酸通量和氧化，导致能量效率低下，进而可能促进氧化应激和轴突退化。我们的研究结果强调，需要进一步研究MCT1和乳酸代谢作为治疗靶点在维持衰老大脑白质完整性和轴突功能方面的作用。
