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

Marina Makrecka-Kuka, Kristine Volska, Unigunde Antone, Reinis Vilskersts, Solveiga Grinberga, Dace Bandere, Edgars Liepinsh, Maija Dambrova

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

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 120 mg/kg for 8 weeks increased TMAO concentration in plasma and cardiac tissues 22–23 times to about 15 μM and 11 nmol/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.

Original languageEnglish
Pages (from-to)32-38
Number of pages7
JournalToxicology Letters
Volume267
DOIs
Publication statusPublished - 5 Feb 2017

Keywords

  • Cardiac mitochondria
  • Energy metabolism
  • Reactive oxygen species
  • Trimethylamine N-oxide

Field of Science

  • 3.1 Basic medicine

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

Fingerprint

Dive into the research topics of 'Trimethylamine N-oxide impairs pyruvate and fatty acid oxidation in cardiac mitochondria'. Together they form a unique fingerprint.

Cite this