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

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 DES-E439K 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 DES-E439K mutation. We show that mutant cardiomyocytes reproduce critical defects in mitochondrial architecture, respiratory capacity and metabolic activity as observed in patient's 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.

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

“…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).…”

“…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). Mitochondrial alterations in desmin mutant and null cells have been the focus of many studies and reviews suggesting that respiration parameters tend to decrease which can be one explanation for cardiomyocyte dysfunction and altered functionality (Alam et al, 2018; Maggi et al, 2021; Smolina et al, 2020).…”