Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia.

Esmeralda Alonso-Barroso,Belén Pérez,Lourdes Ruiz Desviat,Eva Richard

doi:10.3390/ijms22031161

Abstract

Propionic acidemia (PA), one of the most frequent life-threatening organic acidemias, is caused by mutations in either the PCCA or PCCB genes encoding both subunits of the mitochondrial propionyl-CoA carboxylase (PCC) enzyme. Cardiac alterations (hypertrophy, dilated cardiomyopathy, long QT) are one of the major causes of mortality in patients surviving the neonatal period. To overcome limitations of current cellular models of PA, we generated induced pluripotent stem cells (iPSCs) from a PA patient with defects in the PCCA gene, and successfully differentiated them into cardiomyocytes. PCCA iPSC-derived cardiomyocytes exhibited reduced oxygen consumption, an accumulation of residual bodies and lipid droplets, and increased ribosomal biogenesis. Furthermore, we found increased protein levels of HERP, GRP78, GRP75, SIG-1R and MFN2, suggesting endoplasmic reticulum stress and calcium perturbations in these cells. We also analyzed a series of heart-enriched miRNAs previously found deregulated in the heart tissue of a PA murine model and confirmed their altered expression. Our novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.

Highlights

To date, there is no cure for organic acidemias/acidurias (OAs), which are a group of rare inherited metabolic diseases characterized by the excessive accumulation of organic acids in body fluids [1]
The most frequent life-threatening OA that is strongly associated with cardiac complications is propionic acidemia (PA, MIM#606054), which is caused by the deficiency of propionyl-CoA carboxylase (PCC)
We described the characterization of cardiomyocytes derived from the PCCA induced pluripotent stem cells (iPSCs) line (PCCA iPSC-CMs) and the analysis of specific pathways potentially involved in cardiac Propionic acidemia (PA) physiopathology

Summary

Introduction

There is no cure for organic acidemias/acidurias (OAs), which are a group of rare inherited metabolic diseases characterized by the excessive accumulation of organic acids in body fluids [1]. OAs are severe diseases that can affect multiple organ systems; many of them cause cardiac dysfunction. The most frequent life-threatening OA that is strongly associated with cardiac complications is propionic acidemia (PA, MIM#606054), which is caused by the deficiency of propionyl-CoA carboxylase (PCC). Cardiac complications account for significant morbidity and mortality in PA patients, most commonly in the form of cardiomyopathy and prolonged QT intervals [2,3]. The available evidence suggests that dilated cardiomyopathy and prolonged QT are a secondary consequence of PCC dysfunction. No specific biochemical marker related to cardiomyopathy development has to date been identified. The ultimate mechanism for cardiac alterations in PA remains unclear and is likely multifactorial

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