Duberley K E, Heales S J R, Abramov A Y, Chalasani A, Land J M, Rahman S, Hargreaves I P
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Neurometabolic Unit, National Hospital, London, UK; Department of Clinical Pathology and Metabolic Unit, Great Ormond Street Hospital for Children, London, UK.
Int J Biochem Cell Biol. 2014 May;50:60-3. doi: 10.1016/j.biocel.2014.02.003. Epub 2014 Feb 15.
Primary Coenzyme Q10 (CoQ10) deficiency is an autosomal recessive disorder with a heterogeneous clinical presentation. Common presenting features include both muscle and neurological dysfunction. Muscle abnormalities can improve, both clinically and biochemically following CoQ10 supplementation, however neurological symptoms are only partially ameliorated. At present, the reasons for the refractory nature of the neurological dysfunction remain unknown. In order to investigate this at the biochemical level we evaluated the effect of CoQ10 treatment upon a previously established neuronal cell model of CoQ10 deficiency. This model was established by treatment of human SH-SY5Y neuronal cells with 1 mM para-aminobenzoic acid (PABA) which induced a 54% decrease in cellular CoQ10 status. CoQ10 treatment (2.5 μM) for 5 days significantly (p<0.0005) decreased the level of mitochondrial superoxide in the CoQ10 deficient neurons. In addition, CoQ10 treatment (5 μM) restored mitochondrial membrane potential to 90% of the control level. However, CoQ10 treatment (10 μM) was only partially effective at restoring mitochondrial electron transport chain (ETC) enzyme activities. ETC complexes II/III activity was significantly (p<0.05) increased to 82.5% of control levels. ETC complexes I and IV activities were restored to 71.1% and 77.7%, respectively of control levels. In conclusion, the results of this study have indicated that although mitochondrial oxidative stress can be attenuated in CoQ10 deficient neurons following CoQ10 supplementation, ETC enzyme activities appear partially refractory to treatment. Accordingly, treatment with >10 μM CoQ10 may be required to restore ETC enzyme activities to control level. Accordingly, these results have important implication for the treatment of the neurological presentations of CoQ10 deficiency and indicate that high doses of CoQ10 may be required to elicit therapeutic efficacy.
原发性辅酶Q10（CoQ10）缺乏症是一种常染色体隐性疾病，临床表现具有异质性。常见的症状包括肌肉和神经功能障碍。补充CoQ10后，肌肉异常在临床和生化方面均可改善，然而神经症状仅部分得到缓解。目前，神经功能障碍难治性的原因尚不清楚。为了在生化水平上对此进行研究，我们评估了CoQ10治疗对先前建立的CoQ10缺乏神经元细胞模型的影响。该模型是通过用1 mM对氨基苯甲酸（PABA）处理人SH-SY5Y神经元细胞建立的，这导致细胞CoQ10水平降低了54%。用2.5 μM CoQ10处理5天可显著（p<0.0005）降低CoQ10缺乏神经元中线粒体超氧化物的水平。此外，用5 μM CoQ10处理可使线粒体膜电位恢复到对照水平的90%。然而，用10 μM CoQ10处理在恢复线粒体电子传递链（ETC）酶活性方面仅部分有效。ETC复合物II/III活性显著（p<0.05）增加至对照水平的82.5%。ETC复合物I和IV活性分别恢复到对照水平的71.1%和77.7%。总之，本研究结果表明，尽管补充CoQ10后CoQ10缺乏神经元中的线粒体氧化应激可得到减轻，但ETC酶活性似乎对治疗部分难治。因此，可能需要用>10 μM CoQ10进行治疗才能将ETC酶活性恢复到对照水平。因此，这些结果对CoQ10缺乏症神经症状的治疗具有重要意义，并表明可能需要高剂量的CoQ10才能产生治疗效果。
