Pro-longevity natural compounds as suppressors of mitochondrial complex I associated diseases

在过去的几十年里，线粒体功能障碍，归因于线粒体DNA或核DNA的突变，已被确定为许多神经代谢发育障碍的原因。不幸的是，这些疾病大多危及生命，没有有效的治疗方法，因此迫切需要开发合适的疾病模型和工具来促进我们对疾病发病机制的了解，并寻找有针对性的治疗方法。与遗传干预相比，饮食干预尤其可能提供更具可塑性和可行性的治疗方法。多亏了我的第一笔DFG赠款，我们在表型、代谢和分子水平上广泛描述了线粒体应激的双峰适应反应，特别关注动物神经元和线粒体的变化。利用不同程度线粒体应激产生的非常可重复性和离散的动物表型，我们建立了一个自动显微镜平台，用于高含量筛选，以确定通过线粒体发挥作用的干预措施。我们还开发了不同的线虫线粒体疾病模型，并重点研究了与复杂I缺乏相关的Leigh综合征模型：我们广泛地描述了动物的线粒体和神经元变化，并确定叶黄素是潜在的疾病抑制因子。为了跟进这些发现，这项更新建议的总体目标是利用我们的线虫复杂I缺乏症模型来表征叶黄素的作用模式，并寻找新的可能的疾病抑制因子。我们的目标将实现以下三个截然不同但相互关联的目标，这三个目标使用互补的模型系统和最先进的方法：1)揭示叶黄素在优雅线虫中保护作用的作用模式2)验证叶黄素在哺乳动物疾病模型中的保护作用3)在线虫中确定其他复杂的i相关疾病的抑制因子基于我们的发现，我们将专门揭示叶黄素对突触功能的活性并验证其在哺乳动物神经系统中的活性。此外，我们将在其他复杂I缺陷线虫模型上测试叶黄素的拯救作用，并将评估其他有利于长寿的天然化合物确实可能起到疾病抑制作用的假设。我们的项目有望为未来在其他哺乳动物模型以及最终在人类身上进行测试提供新的治疗方法，这可能会导致治疗其他不可治愈的疾病。我们设想这样一种筛查方法将是合适和方便的，以确定潜在有益于罕见和常见疾病的新疗法，这些疾病归因于线粒体功能障碍。因此，这项研究的结果将直接影响基础研究，但最终也将对人类健康和医疗保健系统产生影响。

Over the last few decades, mitochondrial dysfunction, ascribed to mutations in either mitochondrial DNA or nuclear DNA, has been established as a cause for numerous neuro-metabolic developmental disorders. Unfortunately most of these diseases are life-threatening and do not have effective cures thus imposing an urgent need to develop appropriate disease models and tools to advance our understanding of disease pathogenesis and search for targeted therapeutics. Dietary interventions may especially provide more malleable and feasible therapeutic approaches than genetic interventions. Thanks to my first DFG grant we extensively characterized bimodal adaption responses to mitochondrial stress at phenotypic, metabolic and molecular levels, with special focus on animal neuronal and mitochondrial changes. Exploiting the very reproducible and discrete animal phenotypes arising from different degrees of mitochondrial stress, we established an automated microscopy platform for high content screening to identify interventions acting through mitochondria. We also developed different C. elegans models for mitochondrial disorders and focused on models of Leigh’s Syndrome associated with Complex I deficiency: we extensively characterized animals’ mitochondrial and neuronal alterations and identified Lutein as a potential disease suppressor. To follow up on these findings, the overall aim of this renewal proposal is to exploit our C. elegans models for Complex I deficiency to characterize mode of action of Lutein and to search for novel possible diseases suppressors. Our goal will be achieved following three distinct but interrelated objectives, which uses complementary model systems and state of the art methodologies:1) To unravel mode of action of Lutein protective effects in C. elegans2) To validate Lutein protective effects in mammalian disease models3) To identify suppressors of other Complex I-associated disease in C. elegansBased on our findings we will specifically unravel the activity of Lutein on synaptic functionality and validate it mammalian neuronal systems. Moreover, we will test Lutein rescuing effect on other Complex I deficient C. elegans models and will assess the hypothesis that other pro-longevity natural compounds may indeed act as diseases suppressors. Our project is expected to suggest novel therapeutics for future testing in additional mammalian models and eventually humans, which could lead to treatment of otherwise non-curable disorders. We envision such a screening approach to be suitable and convenient to identify novel therapeutics potentially beneficial for both rare and common diseases ascribed to mitochondrial dysfunction. Results obtained with this study will thus directly impact on basic research, but will also eventually have repercussion on human health and healthcare system.