Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland 21201.
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
J Neurosci. 2020 Jun 3;40(23):4609-4619. doi: 10.1523/JNEUROSCI.1632-17.2020. Epub 2020 Apr 29.
Idebenone is a synthetic quinone that on reduction in cells can bypass mitochondrial Complex I defects by donating electrons to Complex III. The drug is used clinically to treat the Complex I disease Leber's hereditary optic neuropathy (LHON), but has been less successful in clinical trials for other neurodegenerative diseases. NAD(P)H:quinone oxidoreductase 1 (NQO1) appears to be the main intracellular enzyme catalyzing idebenone reduction. However, NQO1 is not universally expressed by cells of the brain. Using primary rat cortical cells pooled from both sexes, we tested the hypotheses that the level of endogenous NQO1 activity limits the ability of neurons, but not astrocytes, to use idebenone as an electron donor to support mitochondrial respiration. We then tested the prediction that NQO1 induction by pharmacological activation of the transcription factor nuclear erythroid 2-related factor 2 (Nrf2) enables idebenone to bypass Complex I in cells with poor NQO1 expression. We found that idebenone stimulated respiration by astrocytes but reduced the respiratory capacity of neurons. Importantly, idebenone supported mitochondrial oxygen consumption in the presence of a Complex I inhibitor in astrocytes but not neurons, and this ability was reversed by inhibiting NQO1. Conversely, recombinant NQO1 delivery to neurons prevented respiratory impairment and conferred Complex I bypass activity. Nrf2 activators failed to increase NQO1 in neurons, but carnosic acid induced NQO1 in COS-7 cells that expressed little endogenous enzyme. Carnosic acid-idebenone combination treatment promoted NQO1-dependent Complex I bypass activity in these cells. Thus, combination drug strategies targeting NQO1 may promote the repurposing of idebenone for additional disorders. Idebenone is used clinically to treat loss of visual acuity in Leber's hereditary optic neuropathy. Clinical trials for several additional diseases have failed. This study demonstrates a fundamental difference in the way idebenone affects mitochondrial respiration in cortical neurons compared with cortical astrocytes. Cortical neurons are unable to use idebenone as a direct mitochondrial electron donor due to NQO1 deficiency. Our results suggest that idebenone behaves as an NQO1-dependent prodrug, raising the possibility that lack of neuronal NQO1 activity has contributed to the limited efficacy of idebenone in neurodegenerative disease treatment. Combination therapy with drugs able to safely induce NQO1 in neurons, as well as other brain cell types, may be able to unlock the neuroprotective therapeutic potential of idebenone or related quinones.
依达拉奉是一种合成的醌类物质，在细胞内还原时可以通过将电子传递给复合物 III 来绕过线粒体复合物 I 的缺陷。该药物临床上用于治疗复合物 I 疾病——莱伯遗传性视神经病变（LHON），但在治疗其他神经退行性疾病的临床试验中效果较差。烟酰胺腺嘌呤二核苷酸（磷酸）：醌氧化还原酶 1（NQO1）似乎是催化依达拉奉还原的主要细胞内酶。然而，NQO1 并非大脑细胞普遍表达。我们使用来自两性的原代大鼠皮质细胞进行测试，以检验以下假设：内源性 NQO1 活性水平限制了神经元而不是星形胶质细胞将依达拉奉用作支持线粒体呼吸的电子供体的能力。然后，我们测试了这样一种预测，即通过转录因子核红细胞 2 相关因子 2（Nrf2）的药理学激活诱导 NQO1，使依达拉奉能够绕过表达低水平 NQO1 的细胞中的复合物 I。我们发现，依达拉奉刺激星形胶质细胞的呼吸，但降低神经元的呼吸能力。重要的是，依达拉奉在存在复合物 I 抑制剂的情况下支持星形胶质细胞中的线粒体耗氧，但不能支持神经元，而抑制 NQO1 则逆转了这种能力。相反，将重组 NQO1 递送至神经元可防止呼吸受损并赋予复合物 I 旁路活性。Nrf2 激活剂未能增加神经元中的 NQO1，但 carnosic 酸诱导了表达少量内源性酶的 COS-7 细胞中的 NQO1。Carnosic 酸-依达拉奉联合治疗促进了这些细胞中依赖 NQO1 的复合物 I 旁路活性。因此，针对 NQO1 的联合药物策略可能会促进依达拉奉在其他疾病中的重新应用。依达拉奉临床上用于治疗莱伯遗传性视神经病变引起的视力丧失。几项针对其他疾病的临床试验均告失败。本研究表明，依达拉奉对皮质神经元和皮质星形胶质细胞中线粒体呼吸的影响方式存在根本差异。由于 NQO1 缺乏，皮质神经元无法将依达拉奉用作直接的线粒体电子供体。我们的结果表明，依达拉奉表现为依赖 NQO1 的前药，这增加了神经元中 NQO1 活性缺乏可能导致依达拉奉在神经退行性疾病治疗中的疗效有限的可能性。与能够安全诱导神经元以及其他脑细胞类型中 NQO1 的药物联合治疗，可能能够释放依达拉奉或相关醌类物质的神经保护治疗潜力。
