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.

丙酸血症 （PA） 由 PCCA 或 PCCB 变体引起，表现为危及生命的心肌病和心律失常，病理生理学尚不清楚。在这项工作中，通过稳定同位素示踪分析研究了啮齿动物心脏和人多能干细胞衍生的心肌细胞中的丙酰辅酶 A 代谢。令人惊讶的是，肠道微生物组衍生的丙酸盐而不是产丙氨基酸（缬氨酸、异亮氨酸、苏氨酸和蛋氨酸）或奇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 阻碍了肝脏丙酸盐的处置，提高了循环丙酸盐。长时间的丙酸盐暴露在 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，升高的循环丙酸盐可能会导致 PA 患者心脏的氧化损伤和功能障碍。