title: 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.
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia. Electronic address: makrecka@farm.osi.lv.
authors.forename: Marina
authors.initials: M
authors.lastname: Makrecka-Kuka
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia; Riga Stradins University, Faculty of Pharmacy, Dzirciema Str. 16, Riga, LV-1007, Latvia.
authors.forename: Kristine
authors.initials: K
authors.lastname: Volska
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia.
authors.forename: Unigunde
authors.initials: U
authors.lastname: Antone
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia; Riga Stradins University, Faculty of Pharmacy, Dzirciema Str. 16, Riga, LV-1007, Latvia.
authors.forename: Reinis
authors.initials: R
authors.lastname: Vilskersts
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia.
authors.forename: Solveiga
authors.initials: S
authors.lastname: Grinberga
authors.affiliation: Riga Stradins University, Faculty of Pharmacy, Dzirciema Str. 16, Riga, LV-1007, Latvia.
authors.forename: Dace
authors.initials: D
authors.lastname: Bandere
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia.
authors.forename: Edgars
authors.initials: E
authors.lastname: Liepinsh
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, LV-1006, Latvia; Riga Stradins University, Faculty of Pharmacy, Dzirciema Str. 16, Riga, LV-1007, Latvia.
authors.forename: Maija
authors.initials: M
authors.lastname: Dambrova
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D005227:Fatty Acids / Q000378:metabolism*; D008297:Male; D008744:Methylamines / Q000633:toxicity*; D008813:Mice, Inbred ICR; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D019289:Pyruvic Acid / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D008744:Methylamines; D017382:Reactive Oxygen Species; D019289:Pyruvic Acid; C005855:trimethyloxamine
keywords: Cardiac mitochondria; Energy metabolism; Reactive oxygen species; Trimethylamine N-oxide