Propionate-induced changes in cardiac metabolism, notably CoA trapping, are not altered byl-carnitine

Abstract

High concentrations of propionate and its metabolites are found in several diseases that are often associated with the development of cardiac dysfunction, such as obesity, diabetes, propionic acidemia, and methylmalonic acidemia. In the present work, we employed a stable isotope-based metabolic flux approach to understand propionate-mediated perturbation of cardiac energy metabolism. Propionate led to accumulation of propionyl-CoA (increased by ~101-fold) and methylmalonyl-CoA (increased by 36-fold). This accumulation caused significant mitochondrial CoA trapping and inhibited fatty acid oxidation. The reduced energy contribution from fatty acid oxidation was associated with increased glucose oxidation. The enhanced anaplerosis of propionate and CoA trapping altered the pool sizes of tricarboxylic acid cycle (TCA) metabolites. In addition to being an anaplerotic substrate, the accumulation of proprionate-derived malate increased the recycling of malate to pyruvate and acetyl-CoA, which can enter the TCA for energy production. Supplementation of 3 mM l-carnitine did not relieve CoA trapping and did not reverse the propionate-mediated fuel switch. This is due to new findings that the heart appears to lack the specific enzyme catalyzing the conversion of short-chain (C and C) dicarboxylyl-CoAs to dicarboxylylcarnitines. The discovery of this work warrants further investigation on the relevance of dicarboxylylcarnitines, especially C and C dicarboxylylcarnitines, in cardiac conditions such as heart failure.

Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart

“…The hearts were allowed to beat spontaneously throughout the perfusion. All heart perfusions underwent an initial 15-min equilibration period with Krebs Ringer bicarbonate buffer containing 119 mM NaCl, 4.8 mM KCl, 2.6 mM CaCl 2 , 1.2 mM KH 2 PO 4 , 1.2 mM MgSO 4 , 25 mM NaHCO 3 , 11 mM glucose, and 0.05 mM L-carnitine at a flow rate of 12 ml/min for rats or 1.5 ml/min for mice [51][52][53] . At the end of each perfusion, hearts were immediately freeze-clamped in liquid nitrogen using the Wollenberger technique and stored at −80°C for further analysis.…”

Mutant IDH and non-mutant chondrosarcomas display distinct cellular metabolomes

“…The derivatized samples were centrifuged for 5 min at 20,000× g , and the supernatants were transferred to GC vials for GC-MS analysis. A modified GC-MS method was employed [ 21 ]. The injection volume was 1 μL, and samples were injected in splitless mode.…”

The Association Between Changes in Plasma Short-Chain Fatty Acid Concentrations and Hypertension in Children With Chronic Kidney Disease

“…Propionate has been demonstrated to possess anti-inflammatory effects such as the alleviation of cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension through T cell-dependent regulation in an angiotensin II-infused mouse model ( 19 ). However, Wang et al reported that propionate interfered with fatty acid oxidation as a fuel resource for heart due to the lack of specific enzyme-utilizing short-chain (C3, C4) fatty acids in the propionate-perfused heart ( 20 ), suggesting that higher plasma propionate might cause adverse cardiac effects such as heart failure ( 20 ). This finding might explain the frequent association of cardiovascular dysfunction with dramatic increases in circulating concentrations of propionate or its metabolites in certain diseases, such as obesity, diabetes, and non-CAKUT renal diseases (compared with CAKUT) ( 8 – 10 , 21 ).…”