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Metabolic flux analysis in hiPSC-CMs reveals insights into cardiac dysfunction in propionic acidemia
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Metabolic flux analysis in hiPSC-CMs reveals insights into cardiac dysfunction in propionic acidemia
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Journal Article
Metabolic flux analysis in hiPSC-CMs reveals insights into cardiac dysfunction in propionic acidemia
2025
Overview
Propionic acidemia is an inborn error of metabolism caused by mutations in either the
PCCA
or
PCCB
genes. Patients with propionic acidemia experience a range of complications, including life-threatening cardiac dysfunctions. However, the pathological mechanisms underlying propionic acidemia-associated cardiac diseases remain largely unknown. To gain insights into the metabolic alterations in propionic acidemia, we studied human induced pluripotent stem cell-derived cardiomyocytes generated from a patient with propionic acidemia with two pathogenic
PCCA
mutations (
p.Cys616_Val633del
and
p.Gly477Glufs9*
) and from a healthy individual. Using stable isotope-based metabolic flux analysis, we confirmed that the
PCCA
mutations lead to impaired propionyl-CoA carboxylase activity in human induced pluripotent stem cell-derived cardiomyocytes. In addition to being converted to propionylcarnitine, the accumulated propionyl-CoA can also be hydrolyzed to propionate and exported out of the cell, serving as a secondary “pressure valve” to regulate cellular propionyl-CoA levels. Interestingly, the deficiency of propionyl-CoA carboxylase was found to shift fuel metabolism from fatty acid oxidation to increased glucose metabolism human in induced pluripotent stem cell-derived cardiomyocytes from patients with propionic acidemia. This metabolic switch is less energy-efficient and may contribute to the development of chronic cardiac dysfunction in patients with propionic acidemia.
Publisher
Springer International Publishing,Springer Nature B.V
Subject
/ Biomedical and Life Sciences
/ Carbon-Carbon Ligases - genetics
/ Carbon-Carbon Ligases - metabolism
/ Carnitine - analogs & derivatives
/ fuels
/ glucose
/ Humans
/ Induced Pluripotent Stem Cells - cytology
/ Induced Pluripotent Stem Cells - metabolism
/ inherited metabolic diseases
/ Metabolic Flux Analysis - methods
/ Methylmalonyl-CoA Decarboxylase - genetics
/ Methylmalonyl-CoA Decarboxylase - metabolism
/ Mutation
/ Myocytes, Cardiac - metabolism
/ Myocytes, Cardiac - pathology
/ Original
/ patients
/ Propionic Acidemia - genetics
/ Propionic Acidemia - metabolism
