Rimkus Stacey A, Ganetzky Barry, Wassarman David A
Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin.
Department of Genetics, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin.
PLoS One. 2025 Sep 12;20(9):e0332333. doi: 10.1371/journal.pone.0332333. eCollection 2025.
Traumatic brain injury (TBI) initiates secondary cellular damage such as mitochondrial dysfunction, oxidative stress, and neuroinflammation. In neurodegenerative disorders, these stressors are associated with accumulation of lipid droplets (LDs) - organelles that store neutral lipids to provide energy and protect cells from lipid toxicity. However, the regulation of LD metabolism following TBI remains poorly understood. Using a Drosophila melanogaster model, we investigated how TBI influences LD accumulation, particularly in relation to aging and diet, other LD modulatory factors. Confocal microscopy of fly brains at one day after injury showed increases in both LD size and number. The rise in LD number occurred only in flies fed a carbohydrate-rich diet and was absent in those given a ketogenic diet (KD) or water, suggesting that glucose availability is necessary for LD formation post-injury and potentially underlying why KD and water do not elicit the deleterious outcomes observed with carbohydrates. Lipidomic analysis of fly heads further revealed elevated levels of triacylglycerol (TG) species typically stored in LDs, indicating enhanced lipid synthesis post-injury. By seven days post-injury, LD size and number returned to baseline levels observed in uninjured flies and remained stable through 14 days post-injury. However, by 21 days post-injury, uninjured flies showed a marked increase in LD number that was not observed in injured flies, although LD size increased in both groups. These findings suggest that TBI selectively impairs age-dependent production of new LDs without affecting the growth of existing LDs. Importantly, TG levels remained elevated in heads of injured flies, indicating that the reduction in LD number was not due to limited lipid availability. Together, our findings indicate that TBI acutely induces LD formation as a protective response but chronically impairs LD biogenesis, disrupting lipid homeostasis in an age- and diet-dependent manner that may contribute to neurodegeneration.
创伤性脑损伤（TBI）会引发继发性细胞损伤，如线粒体功能障碍、氧化应激和神经炎症。在神经退行性疾病中，这些应激源与脂滴（LDs）的积累有关，脂滴是储存中性脂质以提供能量并保护细胞免受脂质毒性的细胞器。然而，TBI后脂滴代谢的调节仍知之甚少。我们使用果蝇模型研究了TBI如何影响脂滴积累，特别是与衰老、饮食以及其他脂滴调节因子的关系。受伤一天后对果蝇大脑进行共聚焦显微镜检查发现，脂滴的大小和数量均增加。脂滴数量的增加仅发生在喂食富含碳水化合物饮食的果蝇中，而给予生酮饮食（KD）或水的果蝇中则没有，这表明葡萄糖的可用性对于损伤后脂滴的形成是必要的，这可能是KD和水不会引发碳水化合物所观察到的有害结果的潜在原因。对果蝇头部的脂质组分析进一步显示，通常储存在脂滴中的三酰甘油（TG）种类水平升高，表明损伤后脂质合成增强。到受伤后七天，脂滴的大小和数量恢复到未受伤果蝇中观察到的基线水平，并在受伤后14天保持稳定。然而，到受伤后21天，未受伤的果蝇脂滴数量显著增加，而受伤的果蝇中未观察到这种情况，尽管两组的脂滴大小都增加了。这些发现表明，TBI选择性地损害了年龄依赖性新脂滴的产生，而不影响现有脂滴的生长。重要的是，受伤果蝇头部的TG水平仍然升高，表明脂滴数量的减少不是由于脂质可用性有限。总之，我们的研究结果表明，TBI急性诱导脂滴形成作为一种保护反应，但长期损害脂滴生物合成，以年龄和饮食依赖的方式破坏脂质稳态，这可能导致神经退行性变。
