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.

1. Introduction

Desmin-related myofibrillar myopathy (MFM1, OMIM:601419) represents a group of skeletal and cardiac muscle disorders caused by mutations in the desmin-encoding DES gene. Desmin is the major component of intermediate filaments (IFs) in striated and smooth muscle cells and tissues and plays an essential role in the tensile strength and integrity of muscle fibers [1–4]. In humans, about a hundred mutations of the DES gene have been identified which usually disrupt the ability of desmin to form filamentous networks and/or to interact with partner proteins [3, 5]. Consequently, desmin mutations alter the mechanical properties of the desmin network, resulting in multiple functional and structural abnormalities in muscle cells, leading to progressive skeletal myopathy and cardiomyopathy, the most common clinical manifestations of MFM1 [6]. Impairment of desmin network is also closely associated to the etiology of many striated muscle pathologies. It is worth to note that desmin IFs remodeling also occurs when proteostasis is disturbed, during inflammatory process, or during aging [7–9].

Beyond its role in muscle cell integrity and organization, several studies conducted with genetically modified cell lines carrying human desmin mutations or in desmin knockout mice indicated that desmin critically modulates mitochondria functions [10–15]. Importantly, it has been noticed that mutated desmin leads to severe mitochondria abnormalities that directly contribute to MFM1 development. Consistent with this finding, abnormalities in the distribution and morphology of mitochondria as well as in their respiratory function have been reported with DES mutations using transiently transfected human or animal cells carrying human DES mutations [15, 16], transgenic mouse hearts with DES mutations [17] as well as human heart and skeletal biopsy samples of MFM1 patients [18–20]. Moreover, several publications describe that DES mutations are associated with Cytochrome c oxidase (COX)-negative fibers.