Pandya Jignesh D, Leung Lai Yee, Yang Xiaofang, Flerlage William J, Gilsdorf Janice S, Deng-Bryant Ying, Shear Deborah A
Brain Trauma Neuroprotection Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD, United States.
Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
Front Neurol. 2019 Jun 11;10:605. doi: 10.3389/fneur.2019.00605. eCollection 2019.
Mitochondria constitute a central role in brain energy metabolism, and play a pivotal role in the development of secondary pathophysiology and subsequent neuronal cell death following traumatic brain injury (TBI). Under normal circumstances, the brain consumes glucose as the preferred energy source for adenosine triphosphate (ATP) production over ketones. To understand the comprehensive picture of substrate-specific mitochondrial bioenergetics responses following TBI, adult male rats were subjected to either 10% unilateral penetrating ballistic-like brain injury (PBBI) or sham craniectomy ( = 5 animals per group). At 24 h post-injury, mitochondria were isolated from pooled brain regions (frontal cortex and striatum) of the ipsilateral hemisphere. Mitochondrial bioenergetics parameters were measured in the presence of four sets of metabolic substrates: pyruvate+malate (PM), glutamate+malate (GM), succinate (Succ), and β-hydroxybutyrate+malate (BHBM). Additionally, mitochondrial matrix dehydrogenase activities [i.e., pyruvate dehydrogenase complex (PDHC), alpha-ketoglutarate dehydrogenase complex (α-KGDHC), and glutamate dehydrogenase (GDH)] and mitochondrial membrane-bound dehydrogenase activities [i.e., electron transport chain (ETC) Complex I, II, and IV] were compared between PBBI and sham groups. Furthermore, mitochondrial coenzyme contents, including NAD and FAD, were quantitatively measured in both groups. Collectively, PBBI led to an overall significant decline in the ATP synthesis rates (43-50%; < 0.05 vs. sham) when measured using each of the four sets of substrates. The PDHC and GDH activities were significantly reduced in the PBBI group (42-53%; < 0.05 vs. sham), whereas no significant differences were noted in α-KGDHC activity between groups. Both Complex I and Complex IV activities were significantly reduced following PBBI (47-81%; < 0.05 vs. sham), whereas, Complex II activity was comparable between groups. The NAD and FAD contents were significantly decreased in the PBBI group (27-35%; < 0.05 vs. sham). The decreased ATP synthesis rates may be due to the significant reductions in brain mitochondrial dehydrogenase activities and coenzyme contents observed acutely following PBBI. These results provide a basis for the use of "alternative biofuels" for achieving higher ATP production following severe penetrating brain trauma.
线粒体在脑能量代谢中起核心作用，在创伤性脑损伤（TBI）后的继发性病理生理发展及随后的神经元细胞死亡过程中发挥关键作用。在正常情况下，大脑将葡萄糖作为产生三磷酸腺苷（ATP）的首选能量来源，而非酮类。为了解TBI后底物特异性线粒体生物能量学反应的全貌，成年雄性大鼠接受了10%单侧穿透性弹道样脑损伤（PBBI）或假颅骨切除术（每组n = 5只动物）。损伤后24小时，从同侧半球的合并脑区（额叶皮质和纹状体）分离出线粒体。在存在四组代谢底物的情况下测量线粒体生物能量学参数：丙酮酸+苹果酸（PM）、谷氨酸+苹果酸（GM）、琥珀酸（Succ）和β-羟基丁酸+苹果酸（BHBM）。此外，比较了PBBI组和假手术组之间的线粒体基质脱氢酶活性[即丙酮酸脱氢酶复合体（PDHC）、α-酮戊二酸脱氢酶复合体（α-KGDHC）和谷氨酸脱氢酶（GDH）]以及线粒体膜结合脱氢酶活性[即电子传递链（ETC）复合体I、II和IV]。此外，还对两组中的线粒体辅酶含量，包括NAD和FAD进行了定量测量。总体而言，当使用四组底物中的每一组进行测量时，PBBI导致ATP合成速率总体显著下降（43 - 50%；与假手术组相比，P < 0.05）。PBBI组中PDHC和GDH活性显著降低（42 - 53%；与假手术组相比，P < 0.05），而两组之间α-KGDHC活性未观察到显著差异。PBBI后复合体I和复合体IV活性均显著降低（47 - 81%；与假手术组相比，P < 0.05），而两组之间复合体II活性相当。PBBI组中NAD和FAD含量显著降低（27 - 35%；与假手术组相比，P < 0.05）。ATP合成速率降低可能是由于PBBI后急性观察到的脑线粒体脱氢酶活性和辅酶含量显著降低。这些结果为在严重穿透性脑外伤后使用“替代生物燃料”实现更高的ATP产生提供了依据。
