Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/ijms22031161
Keywords
propionic acidemia; cardiac dysfunction; iPSC; iPSC-derived cardiomyocytes; disease model
Funding
- Propionic Acidemia Foundation [PAF107]
- Spanish Ministry of Economy, Industry and Competitiveness Agencia Estatal de Investigacion and European Regional Development Fund (Fondos Feder) [SAF2016-76004-R]
- Spanish Ministry of Science and Innovation [PID2019105344RB-I00/AEI/10.13039/501100011033]
- Fundacion Isabel Gemio [LCF/PR/PR16/11110018]
- Fundacion La Caixa
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Propionic acidemia (PA) is a common life-threatening organic acidemia caused by mutations in PCCA or PCCB genes. Cardiac alterations are a major cause of mortality in PA patients. Study using iPSC derived cardiomyocytes from a PA patient showed characteristics such as reduced oxygen consumption and endoplasmic reticulum stress.
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.
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