Recent Advances in Modeling Mitochondrial Cardiomyopathy Using Human Induced Pluripotent Stem Cells

Abstract

Around one third of patients with mitochondrial disorders develop a kind of cardiomyopathy. In these cases, severity is quite variable ranging from asymptomatic status to severe manifestations including heart failure, arrhythmias, and sudden cardiac death. ATP is primarily generated in the mitochondrial respiratory chain via oxidative phosphorylation by utilizing fatty acids and carbohydrates. Genes in both the nuclear and the mitochondrial DNA encode components of this metabolic route and, although mutations in these genes are extremely rare, the risk to develop cardiac symptoms is significantly higher in this patient cohort. Additionally, infants with cardiovascular compromise in mitochondrial deficiency display a worse late survival compared to patients without cardiac symptoms. At this point, the mechanisms behind cardiac disease progression related to mitochondrial gene mutations are poorly understood and current therapies are unable to substantially restore the cardiac performance and to reduce the disease burden. Therefore, new strategies are needed to uncover the pathophysiological mechanisms and to identify new therapeutic options for mitochondrial cardiomyopathies. Here, human induced pluripotent stem cell (iPSC) technology has emerged to provide a suitable patient-specific model system by recapitulating major characteristics of the disease in vitro, as well as to offer a powerful platform for pre-clinical drug development and for the testing of novel therapeutic options. In the present review, we summarize recent advances in iPSC-based disease modeling of mitochondrial cardiomyopathies and explore the patho-mechanistic insights as well as new therapeutic approaches that were uncovered with this experimental platform. Further, we discuss the challenges and limitations of this technology and provide an overview of the latest techniques to promote metabolic and functional maturation of iPSC-derived cardiomyocytes that might be necessary for modeling of mitochondrial disorders.

Keywords: heteroplasmy; iPSC-derived cardiomyocytes; induced pluripotent stem cells (hiPSCs); mitochondrial cardiomyopathy; mitochondrial disease; mtDNA.

FIGURE 1

Schematic representation of mitochondria-associated genes involved in protein synthesis and complex formation of the oxidative phosphorylation and ATP synthesis. The table summarizes the most important OXPHOS subunit and assembly proteins in human cells. mtDNA indicates mitochondrial DNA; nDNA, nuclear DNA; rRNA, ribosomal RNA; tRNA, transfer RNA; FA, fatty acids; CI, Complex I or NADH ubiquinone oxidoreductase; CII, Complex II or succinate dehydrogenase; CIII, Complex III or ubiquinol-cytochrome c oxidoreductase; CIV, Complex IV or cytochrome c oxidase; CV, Complex V or ATP synthase; CoQ, coenzyme Q10 and Cyt C, cytochrome c.

FIGURE 2

Impact of mtDNA heteroplasmy levels on cardiomyocyte pathology. mtDNA heteroplasmy associated to pathogenic variant load in iPSCs is typically preserved during cardiomyocyte differentiation, promoting poor mitochondrial performance and cardiac remodeling when mtDNA variant load exceeds a certain.

FIGURE 3

Impact of mitochondrial dysfunction on cardiomyocyte pathology. Mitochondrial dysfunction, either caused by gene mutations in mitochondrial genes (primary mitochondrial cardiomyopathy) or as a consequence of other cellular disturbances (such as calcium overload or lipotoxicity), promotes an energy depletion as well as increased ROS production. Poor bioenergetic capacity and oxidative stress provoke, among others, changes in cytosolic calcium handling, electrophysiological defects, reduced contractile performance, sarcomeric re-arrangements, re-expression of fetal genes, cardiac remodeling and apoptosis.