Impact of mitochondrial DYNAMIcs and genome instability on the development ofage-related CArdiac disorders

心血管疾病是全世界死亡的主要原因之一，年龄是主要风险因素之一。虽然起源是多因素的，但许多研究指出了线粒体的关键作用。这些细胞器是许多关键代谢过程的核心，它们有自己的基因组（mtDNA），在心肌细胞中有数千个拷贝，在衰老过程中积累了大量的缺失。一旦这些突变达到临界阈值，细胞就会表现出严重的线粒体功能障碍，导致缺陷细胞镶嵌在“正常”细胞中。使用一种新的小鼠模型，在心脏中概括了这一过程，我们已经证明mtDNA不稳定与心律失常有关。因此，减少mtDNA突变积累的方法将导致新的治疗策略的发展。线粒体动力学（融合/裂变）已被证明影响突变mtDNA拷贝的负荷。在这个项目中，使用mtDNA完整性受损和线粒体融合或裂变受损的小鼠，我们将确定mtDNA不稳定性和随后的线粒体缺陷马赛克模式如何导致与年龄相关的心血管疾病的严重程度，以及调节线粒体动力学是否会对这些疾病的结果产生影响。

Cardiovascular diseases are among the leading causes of death worldwide, with age being one of the main risk factors. Although the origins are multifactorial, many studies point to a critical role of mitochondria. These organelles are central to many crucial metabolic processes and have their own genome (mtDNA), present in thousands of copies in a cardiomyocyte, which accumulates large deletions during aging. Once these mutations reach a critical threshold, cells will display severe mitochondrial dysfunction, giving rise to a mosaic pattern of defective cells embedded among “normal” cells. Using a novel mouse model that recapitulates this process in the heart, we have shown that mtDNA instability is involved in cardiac arrhythmias. Thus, approaches reducing the accumulation of mtDNA mutations will lead to the development of new therapeutic strategies. Mitochondrial dynamics (fusion/fission) has been shown to impact the load of mutated mtDNA copies. In this project, using mice with compromised mtDNA integrity and impaired mitochondrial fusion or fission, we will determine how mtDNA instability and the ensuing mosaic pattern of mitochondrial deficiency contributes to the severity of age-related cardiovascular diseases, and whether modulating mitochondrial dynamics could have an impact on the outcomes of such pathologies.