Kargaran Parisa K, Mosqueira Diogo, Kozicz Tamas
Department of Cardiovascular Medicine, Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, United States.
Division of Cancer & Stem Cells, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.
Front Cardiovasc Med. 2021 Jan 18;7:604581. doi: 10.3389/fcvm.2020.604581. eCollection 2020.
Mitochondrial medicine is an exciting and rapidly evolving field. While the mitochondrial genome is small and differs from the nuclear genome in that it is circular and free of histones, it has been implicated in neurodegenerative diseases, type 2 diabetes, aging and cardiovascular disorders. Currently, there is a lack of efficient treatments for mitochondrial diseases. This has promoted the need for developing an appropriate platform to investigate and target the mitochondrial genome. However, developing these therapeutics requires a model system that enables rapid and effective studying of potential candidate therapeutics. In the past decade, induced pluripotent stem cells (iPSCs) have become a promising technology for applications in basic science and clinical trials, and have the potential to be transformative for mitochondrial drug development. Engineered iPSC-derived cardiomyocytes (iPSC-CM) offer a unique tool to model mitochondrial disorders. Additionally, these cellular models enable the discovery and testing of novel therapeutics and their impact on pathogenic mtDNA variants and dysfunctional mitochondria. Herein, we review recent advances in iPSC-CM models focused on mitochondrial dysfunction often causing cardiovascular diseases. The importance of mitochondrial disease systems biology coupled with genetically encoded NAD/NADH sensors is addressed toward developing an translational approach to establish effective therapies.
线粒体医学是一个令人兴奋且发展迅速的领域。线粒体基因组虽小，且与核基因组不同，它呈环状且不含组蛋白，但它已被认为与神经退行性疾病、2型糖尿病、衰老及心血管疾病有关。目前，线粒体疾病缺乏有效的治疗方法。这促使人们需要开发一个合适的平台来研究线粒体基因组并将其作为靶点。然而，开发这些疗法需要一个能够快速有效地研究潜在候选疗法的模型系统。在过去十年中，诱导多能干细胞（iPSC）已成为基础科学和临床试验中一项很有前景的技术，并且有可能为线粒体药物开发带来变革。工程化的iPSC来源的心肌细胞（iPSC-CM）为模拟线粒体疾病提供了一种独特的工具。此外，这些细胞模型能够发现和测试新型疗法及其对致病性线粒体DNA（mtDNA）变体和功能失调线粒体的影响。在此，我们综述了iPSC-CM模型的最新进展，这些模型聚焦于常导致心血管疾病的线粒体功能障碍。在开发建立有效疗法的转化方法方面，探讨了线粒体疾病系统生物学与基因编码的NAD/NADH传感器的重要性。
