Gureev Artem P, Nesterova Veronika V, Babenkova Polina I, Ivanov Mikhail E, Plotnikov Egor Y, Silachev Denis N
Department of Genetics, Cytology and Bioengineering, Voronezh State University, 394018 Voronezh, Russia.
A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia.
Int J Mol Sci. 2025 Mar 22;26(7):2902. doi: 10.3390/ijms26072902.
Traumatic brain injuries (TBIs) are a serious problem affecting individuals of all ages. Mitochondrial dysfunctions represent a significant form of secondary injury and may serve as a promising target for therapeutic intervention. Our research demonstrated that craniotomy, which precedes the experimental induction of trauma in mice, can cause considerable damage to mitochondrial DNA (mtDNA), disrupt the regulatory expression of angiogenesis, and increase inflammation. However, the reduction in the mtDNA copy number and glial activation occur only after a direct impact to the brain. We explored two potential therapeutic agents: the dietary supplement L-carnitine-a potential reserve source of ATP for the brain-and the cardiac drug mildronate, which inhibits L-carnitine but activates alternative compensatory pathways for the brain to adapt to metabolic disturbances. We found that L-carnitine injections could protect against mtDNA depletion by promoting mitochondrial biogenesis. However, they also appeared to aggravate inflammatory responses, likely due to changes in the composition of the gut microbiome. On the other hand, mildronate enhanced the expression of genes related to angiogenesis while also reducing local and systemic inflammation. Therefore, both compounds, despite their opposing metabolic effects, have the potential to be used in the treatment of secondary injuries caused by TBI.
创伤性脑损伤（TBI）是一个影响各年龄段人群的严重问题。线粒体功能障碍是继发性损伤的一种重要形式，可能成为有前景的治疗干预靶点。我们的研究表明，在小鼠实验性创伤诱导之前进行的开颅手术，可对线粒体DNA（mtDNA）造成相当大的损伤，破坏血管生成的调控表达，并增加炎症反应。然而，mtDNA拷贝数的减少和胶质细胞激活仅在脑受到直接撞击后才会发生。我们探索了两种潜在的治疗药物：膳食补充剂L-肉碱——大脑潜在的ATP储备来源——以及心脏药物米多君，它抑制L-肉碱但激活大脑适应代谢紊乱的替代补偿途径。我们发现，注射L-肉碱可通过促进线粒体生物合成来防止mtDNA耗竭。然而，它们似乎也会加剧炎症反应，这可能是由于肠道微生物群组成的变化所致。另一方面，米多君增强了与血管生成相关基因的表达，同时还减轻了局部和全身炎症。因此，这两种化合物尽管具有相反的代谢作用，但都有潜力用于治疗由TBI引起的继发性损伤。
