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<p>Propionic acidemia is an inborn error of metabolism caused by mutations in either the <i>PCCA</i> or <i>PCCB</i> 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 <i>PCCA</i> mutations (<i>p.Cys616_Val633del</i> and <i>p.Gly477Glufs9*</i>) and from a healthy individual. Using stable isotope-based metabolic flux analysis, we confirmed that the <i>PCCA</i> 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.</p>

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Metabolic flux analysis in hiPSC-CMs reveals insights into cardiac dysfunction in propionic acidemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月2日

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  • Eva Richard,
  • Hannah Marchuk,
  • Mar Álvarez,
  • Wentao He,
  • Xiaoxin Chen,
  • Lourdes R. Desviat,
  • Guo-Fang Zhang

摘要

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.