Abstract

Beyond the observed alterations in cellular structure and mitochondria, the cellular mechanisms linking genetic mutations to the development of heart failure in patients affected by desmin defects remain unclear due, in part, to the lack of relevant human cardiomyocyte models. We investigated the role of mitochondria using cardiomyocytes derived from human induced pluripotent stem cells carrying the heterozygous DESE439K desmin mutation, that were either isolated from a patient or generated by gene editing. To increase physiological relevance, cells were either cultured on an anisotropic surface to obtain elongated and aligned cardiomyocytes, or as spheroids to create a micro- tissue. When applicable, results were confirmed with heart biopsies from the family harboring DESE439K mutation. We show that mutant cardiomyocytes reproduce critical defects in mitochondrial architecture, respiratory capacity and metabolic activity as observed in patients heart tissue. To challenge the pathological mechanism, normal mitochondria were transferred inside the mutant cardiomyocytes. This treatment restored mitochondrial and contractile functions. This work demonstrates the crucial role of mitochondrial abnormalities in the pathophysiology of desmin-related cardiomyopathy, and opens-up new potential therapeutic perspectives.