%0 Journal Article
%T The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia.
%A Wang Y
%A Zhu S
%A He W
%A Marchuk H
%A Richard E
%A Desviat LR
%A Young SP
%A Koeberl D
%A Kasumov T
%A Chen X
%A Zhang GF
%J Basic Res Cardiol
%V 0
%N 0
%D 2024 Jul 11
%M 38992300
%F 12.416
%R 10.1007/s00395-024-01066-w
%X 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.