Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Mol Genet Metab. 2012 Nov;107(3):375-82. doi: 10.1016/j.ymgme.2012.08.016. Epub 2012 Aug 29.
Mitochondrial dysfunction has been proposed to play an important role in the neuropathology of glutaric acidemia type I (GA I). However, the relevance of bioenergetics disruption and the exact mechanisms responsible for the cortical leukodystrophy and the striatum degeneration presented by GA I patients are not yet fully understood. Therefore, in the present work we measured the respiratory chain complexes activities I-IV, mitochondrial respiratory parameters state 3, state 4, the respiratory control ratio and dinitrophenol (DNP)-stimulated respiration (uncoupled state), as well as the activities of α-ketoglutarate dehydrogenase (α-KGDH), creatine kinase (CK) and Na+, K+-ATPase in cerebral cortex, striatum and hippocampus from 30-day-old Gcdh-/- and wild type (WT) mice fed with a normal or a high Lys (4.7%) diet. When a baseline (0.9% Lys) diet was given, we verified mild alterations of the activities of some respiratory chain complexes in cerebral cortex and hippocampus, but not in striatum from Gcdh-/- mice as compared to WT animals. Furthermore, the mitochondrial respiratory parameters and the activities of α-KGDH and CK were not modified in all brain structures from Gcdh-/- mice. In contrast, we found a significant reduction of Na(+), K(+)-ATPase activity associated with a lower degree of its expression in cerebral cortex from Gcdh-/- mice. Furthermore, a high Lys (4.7%) diet did not accentuate the biochemical alterations observed in Gcdh-/- mice fed with a normal diet. Since Na(+), K(+)-ATPase activity is required for cell volume regulation and to maintain the membrane potential necessary for a normal neurotransmission, it is presumed that reduction of this enzyme activity may represent a potential underlying mechanism involved in the brain swelling and cortical abnormalities (cortical atrophy with leukodystrophy) observed in patients affected by GA I.
线粒体功能障碍被认为在 1 型戊二酸血症（GA I）的神经病理学中发挥重要作用。然而，生物能量学破坏的相关性以及导致 GA I 患者皮质白质营养不良和纹状体变性的确切机制尚不完全清楚。因此，在本研究中，我们测量了呼吸链复合物 I-IV 的活性、线粒体呼吸参数状态 3、状态 4、呼吸控制比和二硝基苯酚（DNP）刺激的呼吸（解偶联状态），以及在 30 天龄的 Gcdh-/-和野生型（WT）小鼠的大脑皮层、纹状体和海马中的α-酮戊二酸脱氢酶（α-KGDH）、肌酸激酶（CK）和 Na+，K+-ATPase 的活性。当给予基础（0.9%Lys）饮食时，我们发现与 WT 动物相比，Gcdh-/-小鼠大脑皮层和海马中的一些呼吸链复合物的活性有轻微改变，但纹状体中没有。此外，Gcdh-/-小鼠的所有脑结构中的线粒体呼吸参数以及α-KGDH 和 CK 的活性均未改变。相比之下，我们发现 Gcdh-/-小鼠大脑皮层中的 Na+，K+-ATPase 活性显著降低，其表达水平也降低。此外，高 Lys（4.7%）饮食并没有加重 Gcdh-/-小鼠在正常饮食下观察到的生化改变。由于 Na+，K+-ATPase 活性对于细胞体积调节和维持正常神经传递所需的膜电位是必需的，因此，假定该酶活性的降低可能代表了参与 GA I 患者脑肿胀和皮质异常（皮质萎缩伴白质营养不良）的潜在潜在机制。
