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

心血管疾病是全世界的主要死亡原因之一，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，并具有自己的基因组（mtDNA），在心肌细胞中存在数千个拷贝，在衰老过程中积累大量缺失。一旦这些突变达到临界阈值，细胞将显示严重的线粒体功能障碍，导致嵌入“正常”细胞中的缺陷细胞的马赛克模式。使用一种新的小鼠模型，在心脏中重现这一过程，我们已经表明，mtDNA的不稳定性参与心律失常。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/分裂）已被证明会影响突变mtDNA拷贝的负荷。在这个项目中，使用线粒体DNA完整性受损和线粒体融合或分裂受损的小鼠，我们将确定线粒体DNA不稳定性和随后的线粒体缺陷镶嵌模式如何导致年龄相关性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病理的结果产生影响。

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.