Zighan Madleen, Arkadir David, Douiev Liza, Keller Guy, Miller Chaya, Saada Ann
Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Neurology, Hadassah Medical Center, Jerusalem, Israel.
Front Mol Biosci. 2022 Aug 12;9:890653. doi: 10.3389/fmolb.2022.890653. eCollection 2022.
Omaveloxolone (RTA408) is a second-generation oleanane triterpenoid Nrf2 inducer with antioxidant and anti-inflammatory properties and was reported to improve mitochondrial bioenergetics. It is currently being tested in medical trials for Friedrich ataxia, a genetic, multi-organ disease involving mitochondrial dysfunction. Thus, omaveloxolone could potentially be beneficial for additional disorders involving mitochondrial dysfunction. To this end, we investigated its effect on primary fibroblasts derived from patients with mitochondrial complex I deficiency, mitochondrial cytochrome oxidase deficiency, and two recessive forms of Parkinson's disease. Patients and control cells were incubated in the presence or absence of 50 nM omaveloxolone for 72 h prior to measurements. Generally, growth on galactose medium and ATP production were unaltered. Mitochondrial membrane potential was slightly but significantly decreased, while reactive oxygen species (ROS) production was variably decreased. Mitochondrial mass and mitochondrial DNA (mtDNA) contents were significantly increased in the patient's cells. These results were partially confirmed by the results of oxygen consumption studies which disclosed increased maximal oxygen consumption rates in most cells and increased energy status in all treated cells. Further investigation is required to explore the precise effect of omaveloxolone on mitochondrial function in disease.
奥马韦洛酮（RTA408）是一种具有抗氧化和抗炎特性的第二代齐墩果烷三萜类Nrf2诱导剂，据报道可改善线粒体生物能量学。目前它正在进行针对弗里德赖希共济失调的医学试验，这是一种涉及线粒体功能障碍的遗传性多器官疾病。因此，奥马韦洛酮可能对其他涉及线粒体功能障碍的疾病有益。为此，我们研究了它对来自线粒体复合物I缺乏症、线粒体细胞色素氧化酶缺乏症患者以及两种隐性帕金森病患者的原代成纤维细胞的影响。在测量前，将患者细胞和对照细胞在有或无50 nM奥马韦洛酮的情况下孵育72小时。一般来说，在半乳糖培养基上的生长和ATP产生未改变。线粒体膜电位略有但显著下降，而活性氧（ROS）产生则有不同程度的下降。患者细胞中的线粒体质量和线粒体DNA（mtDNA）含量显著增加。耗氧研究结果部分证实了这些结果，该研究表明大多数细胞的最大耗氧率增加，所有处理细胞的能量状态增加。需要进一步研究以探索奥马韦洛酮在疾病中对线粒体功能的确切影响。
