Abstract：
Propionic acidemia (PA), arising from PCCA or PCCB variants, manifests as life-threatening cardiomyopathy and arrhythmias, with unclear pathophysiology. In this work, propionyl-CoA metabolism in rodent hearts and human pluripotent stem cell-derived cardiomyocytes was investigated with stable isotope tracing analysis. Surprisingly, gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source. In a Pcca-/-(A138T) mouse model and PA patients, accumulated propionyl-CoA and diminished acyl-CoA synthetase short-chain family member 3 impede hepatic propionate disposal, elevating circulating propionate. Prolonged propionate exposure induced significant oxidative stress in PCCA knockdown HL-1 cells and the hearts of Pcca-/-(A138T) mice. Additionally, Pcca-/-(A138T) mice exhibited mild diastolic dysfunction after the propionate challenge. These findings suggest that elevated circulating propionate may cause oxidative damage and functional impairment in the hearts of patients with PA.
摘要：
丙酸血症(PA),由PCCA或PCCB变体产生，表现为危及生命的心肌病和心律失常，病理生理学不清楚。在这项工作中,用稳定同位素示踪分析研究了啮齿动物心脏和人类多能干细胞衍生的心肌细胞中的丙酰基-CoA代谢。令人惊讶的是,肠道微生物组来源的丙酸盐，而不是丙酸氨基酸(缬氨酸，异亮氨酸,苏氨酸,和蛋氨酸）或奇数链脂肪酸被发现是主要的心脏丙酰辅酶A来源。在Pcca-/-（A138T）小鼠模型和PA患者中，积累的丙酰基辅酶A和减少的酰基辅酶A合成酶短链家族成员3阻碍了肝丙酸处置，升高循环丙酸盐。延长丙酸盐暴露在PCCA敲低HL-1细胞和Pcca-/-（A138T）小鼠的心脏中诱导了显着的氧化应激。此外,Pcca-/-(A138T)小鼠在丙酸盐攻击后表现出轻度舒张功能障碍。这些发现表明，循环丙酸酯的升高可能会导致PA患者心脏的氧化损伤和功能损害。
