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

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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.