Trimethylamine N-oxide impairs pyruvate and fatty acid oxidation in cardiac mitochondria

Abstract

Increased plasma concentration of trimethylamine N-oxide (TMAO), a proatherogenic metabolite, has been linked to adverse cardiovascular outcomes; however, it remains unclear whether TMAO is a biomarker or whether it induces direct detrimental cardiovascular effects. Because altered cardiac energy metabolism and mitochondrial dysfunction play crucial roles in the development of cardiovascular diseases, we hypothesized that increased TMAO concentration may alter mitochondrial energy metabolism. The aim of the present study was to determine the effects of TMAO on cardiac mitochondrial energy metabolism. Acute exposure of cardiac fibers to TMAO decreased LEAK (substrate-dependent) and OXPHOS (oxidative phosphorylation-dependent) mitochondrial respiration with pyruvate and impaired substrate flux via pyruvate dehydrogenase. The administration of TMAO at a dose of 120mg/kg for 8 weeks increased TMAO concentration in plasma and cardiac tissues 22-23 times to about 15μM and 11nmol/g, respectively. Long-term TMAO administration decreased mitochondrial LEAK state respiration with pyruvate by 30% without affecting OXPHOS state respiration. However, no significant changes in mitochondrial reactive oxygen species production were observed after acute exposure of cardiac fibers to TMAO under physiological conditions. In addition, both long-term TMAO administration and acute exposure to TMAO decreased respiration with palmitoyl-CoA indicating impaired β-oxidation. Taken together, our results demonstrate that increased TMAO concentration impairs pyruvate and fatty acid oxidation in cardiac mitochondria. Thus, the accumulation of TMAO in cardiac tissues leads to disturbances in energy metabolism that can increase the severity of cardiovascular events.

A pilot study investigating circulating trimethylamineN‐oxide and its precursors in dogs with degenerative mitral valve disease with or without congestive heart failure

“…Although most studies in humans have focused on TMAO in coronary artery disease, TMAO has been shown to be increased in people with congestive heart failure (CHF) resulting from both ischemic and nonischemic heart disease . Results of 2 recent in vitro studies suggest that TMAO's nonvascular adverse effects on the heart could be the result of decreased cardiomyocyte contractility and intracellular calcium flux or impaired myocardial energy metabolism . Alternatively, increased TMAO may not be a cause of CV pathology but may be the result of inflammation associated with CV disease.…”

CntA oxygenase substrate profile comparison and oxygen dependency of TMA production in Providencia rettgeri

“…Defective or downregulated FMO3 can cause trimethylaminouria or “fish odor syndrome” . The exact mechanism by which TMA/TMAO exercises its influence is not exactly known, although there have been several suggestions: negative influence of TMAO on cholesterol efflux from foam cells ; influence of TMA/TMAO on FMO3, a key known regulator of cholesterol metabolism activity ; possible hypersensitization of platelets by TMAO ; and impairment of pyruvate and fatty acid oxidation in cardiac mitochondria . There is also some controversy about whether TMAO is actually a cause of atherosclerosis or merely a marker of it .…”

Trimethylamine N-oxide Supplementation Abolishes the Cardioprotective Effects of Voluntary Exercise in Mice Fed a Western Diet

“…To assess the effect of voluntary exercise on WD-induced cardiac dysfunction and molecular mechanism, mice were randomly divided into four groups ( n = 10 for each group): (1) normal diet-sedentary (ND-SED), (2) western diet-sedentary (WD-SED), (3) western diet-voluntary exercise (WD-EXE), and (4) western diet-voluntary exercise with TMAO administration (WD-EXE-TMAO). Groups underwent simultaneous diet modification and voluntary exercise training with or without administration of TMAO (120 mg/kg) in drinking water (Makrecka-Kuka et al, 2017 ) for 8 weeks. The ND (Teklad LM-385, Harlan) contained 17% total fat, 0.8% saturated fat, and 0% sucrose, while WD (TD 88137, Harlan) had 42% total fat, 12.8% saturated fat, and 30% sucrose.…”