Cavalcanti-de-Albuquerque Joao Paulo, de-Souza-Ferreira Eduardo, de Carvalho Denise Pires, Galina Antonio
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, 21941-170, Brazil.
Institute of Medical Biochemistry Leopoldo De Meis, Center of Health Science, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Neurochem Res. 2022 Feb;47(2):470-480. doi: 10.1007/s11064-021-03463-2. Epub 2021 Oct 8.
Glucose and oxygen (O) are vital to the brain. Glucose metabolism and mitochondria play a pivotal role in this process, culminating in the increase of reactive O species. Hexokinase (HK) is a key enzyme on glucose metabolism and is coupled to the brain mitochondrial redox modulation by recycling ADP for oxidative phosphorylation (OXPHOS). GABA shunt is an alternative pathway to GABA metabolism that increases succinate levels, a Krebs cycle intermediate. Although glucose and GABA metabolisms are intrinsically connected, their interplay coordinating mitochondrial function is poorly understood. Here, we hypothesize that the HK and the GABA shunt interact to control mitochondrial metabolism differently in the cortex and the hypothalamus. The GABA shunt stimulated mitochondrial O consumption and HO production higher in hypothalamic synaptosomes (HSy) than cortical synaptosomes (CSy). The GABA shunt increased the HK coupled to OXPHOS activity in both population of synaptosomes, but the rate of activation was higher in HSy than CSy. Significantly, malonate and vigabatrin blocked the effects of the GABA shunt in the HK activity coupled to OXPHOS. It indicates that the glucose phosphorylation is linked to GABA and Krebs cycle reactions. Together, these data shed light on the HK and SDH role on the metabolism of each region fed by GABA turnover, which depends on the neurons' metabolic route.
葡萄糖和氧气（O）对大脑至关重要。葡萄糖代谢和线粒体在此过程中起着关键作用，最终导致活性氧物种增加。己糖激酶（HK）是葡萄糖代谢的关键酶，通过循环利用二磷酸腺苷（ADP）进行氧化磷酸化（OXPHOS）与脑线粒体氧化还原调节相关联。γ-氨基丁酸（GABA）分流是GABA代谢的一条替代途径，可增加三羧酸循环中间产物琥珀酸的水平。尽管葡萄糖和GABA代谢在本质上相互关联，但它们协调线粒体功能的相互作用却知之甚少。在此，我们假设HK和GABA分流在皮质和下丘脑以不同方式相互作用以控制线粒体代谢。GABA分流在下丘脑突触体（HSy）中比皮质突触体（CSy）中刺激线粒体氧消耗和过氧化氢（HO）产生的作用更强。GABA分流在两种突触体群体中均增加了与OXPHOS活性相关联的HK，但在HSy中的激活速率高于CSy。值得注意的是，丙二酸和氨己烯酸阻断了GABA分流对与OXPHOS相关联的HK活性的影响。这表明葡萄糖磷酸化与GABA和三羧酸循环反应相关联。总之，这些数据揭示了HK和琥珀酸脱氢酶（SDH）在由GABA周转提供能量的每个区域的代谢中的作用，这取决于神经元的代谢途径。
