Cell Physiology & Pathology Laboratory of R&D Center of Biomedical Photonics, Orel State University, Orel, 302026, Russia.
Laboratory of Genome Editing for Biomedicine and Animal Health, Belgorod State National Research University, Belgorod, 308015, Russia.
Mol Neurobiol. 2023 Jun;60(6):3147-3157. doi: 10.1007/s12035-023-03266-2. Epub 2023 Feb 21.
Alterations in function of hypoxanthine guanine phosphoribosyl transferase (HPRT), one of the major enzymes involved in purine nucleotide exchange, lead to overproduction of uric acid and produce various symptoms of Lesch-Nyhan syndrome (LNS). One of the hallmarks of LNS is maximal expression of HPRT in the central nervous system with the highest activity of this enzyme in the midbrain and basal ganglia. However, the nature of neurological symptoms has yet to be clarified in details. Here, we studied whether HPRT1 deficiency changes mitochondrial energy metabolism and redox balance in murine neurons from the cortex and midbrain. We found that HPRT1 deficiency inhibits complex I-dependent mitochondrial respiration resulting in increased levels of mitochondrial NADH, reduction of the mitochondrial membrane potential, and increased rate of reactive oxygen species (ROS) production in mitochondria and cytosol. However, increased ROS production did not induce oxidative stress and did not decrease the level of endogenous antioxidant glutathione (GSH). Thus, disruption of mitochondrial energy metabolism but not oxidative stress could play a role of potential trigger of brain pathology in LNS.
黄嘌呤鸟嘌呤磷酸核糖转移酶（HPRT）功能的改变，作为嘌呤核苷酸交换的主要酶之一，导致尿酸生成过多，并产生各种 Lesch-Nyhan 综合征（LNS）的症状。LNS 的一个特征是 HPRT 在中枢神经系统中的最大表达，该酶在中脑和基底神经节中的活性最高。然而，神经系统症状的性质尚未详细阐明。在这里，我们研究了 HPRT1 缺乏是否会改变来自大脑皮层和中脑的鼠神经元中线粒体能量代谢和氧化还原平衡。我们发现 HPRT1 缺乏抑制了依赖复合物 I 的线粒体呼吸，导致线粒体 NADH 水平升高，线粒体膜电位降低，线粒体和胞质中活性氧（ROS）的产生速率增加。然而，增加的 ROS 产生并没有诱导氧化应激，也没有降低内源性抗氧化剂谷胱甘肽（GSH）的水平。因此，线粒体能量代谢的破坏而不是氧化应激可能在 LNS 的脑病理学中起潜在触发作用。
