Critical contribution of mitochondria in the development of cardiomyopathy linked to desmin mutation

Abstract

Background Beyond the observed alterations in cellular structure and mitochondria, the mechanisms linking rare genetic mutations to the development of heart failure in patients affected by desmin mutations remain unclear due in part, to the lack of relevant human cardiomyocyte models. Methods To shed light on the role of mitochondria in these mechanisms, we investigated cardiomyocytes derived from human induced pluripotent stem cells carrying the heterozygous DESE439K mutation that were either isolated from a patient or generated by gene editing. To increase physiological relevance, cardiomyocytes were either cultured on an anisotropic micropatterned surface to obtain elongated and aligned cardiomyocytes, or as a cardiac spheroid to create a micro-tissue. Moreover, when applicable, results from cardiomyocytes were confirmed with heart biopsies of suddenly died patient of the same family harboring DESE439K mutation, and post-mortem heart samples from five control healthy donors. Results The heterozygous DESE439K mutation leads to dramatic changes in the overall cytoarchitecture of cardiomyocytes, including cell size and morphology. Most importantly, mutant cardiomyocytes display altered mitochondrial architecture, mitochondrial respiratory capacity and metabolic activity reminiscent of defects observed in patient’s heart tissue. Finally, to challenge the pathological mechanism, we transferred normal mitochondria inside the mutant cardiomyocytes and demonstrated that this treatment was able to restore mitochondrial and contractile functions of cardiomyocytes. Conclusions This work highlights the deleterious effects of DESE439K mutation, demonstrates the crucial role of mitochondrial abnormalities in the pathophysiology of desmin-related cardiomyopathy, and opens up new potential therapeutic perspectives for this disease.

Pathophysiological mechanisms of cardiomyopathies induced by desmin gene variants located in the C‐Terminus of segment 2B

“…The study demonstrated fewer cristae that could explain the decrease in the expression of COXIV, a mitochondrial respiratory chain protein (Hovhannisyan et al, 2024). Furthermore, RNA sequencing showed that iPSC-CMs with the E439K mutation show downregulation of genes that are related to mitochondria, compared to control cells (Hovhannisyan et al, 2024).…”

“…When studying how the p.E439K desmin variant may affect mitochondria in cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs), Hovhannisyan et al concluded that not only are mitochondria physically altered but also functionally. The study demonstrated fewer cristae that could explain the decrease in the expression of COXIV, a mitochondrial respiratory chain protein (Hovhannisyan et al, 2024). Furthermore, RNA sequencing showed that iPSC-CMs with the E439K mutation show downregulation of genes that are related to mitochondria, compared to control cells (Hovhannisyan et al, 2024).…”