Low cardiac content of long-chain acylcarnitines in TMLHE knockout mice prevents ischaemia-reperfusion-induced mitochondrial and cardiac damage

Increased tissue content of long-chain acylcarnitines may induce mitochondrial and cardiac damage by stimulating ROS production. N6-trimethyllysine dioxygenase (TMLD) is the first enzyme in the carnitine/acylcarnitine biosynthesis pathway. Inactivation of the TMLHE gene (TMLHE KO) in mice is expecte...

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Published in:Free radical biology & medicine Vol. 177; pp. 370 - 380
Main Authors: Liepinsh, Edgars, Kuka, Janis, Vilks, Karlis, Svalbe, Baiba, Stelfa, Gundega, Vilskersts, Reinis, Sevostjanovs, Eduards, Goldins, Niks Ricards, Groma, Valerija, Grinberga, Solveiga, Plaas, Mario, Makrecka-Kuka, Marina, Dambrova, Maija
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01.12.2021
Subjects:
Acylcarnitine
Animals
Carnitine - analogs & derivatives
Fatty acid metabolism
Gamma-butyrobetaine
Ischemia
Male
Mice
Mice, Knockout
Mitochondria, Heart
Myocardial infarction
PUFA
Reperfusion
Trimethyllysine
Myocardial infarction
Acylcarnitine
Trimethyllysine
Gamma-butyrobetaine
Fatty acid metabolism
PUFA
ISSN:0891-5849, 1873-4596, 1873-4596
Online Access:Get full text
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Summary:Increased tissue content of long-chain acylcarnitines may induce mitochondrial and cardiac damage by stimulating ROS production. N6-trimethyllysine dioxygenase (TMLD) is the first enzyme in the carnitine/acylcarnitine biosynthesis pathway. Inactivation of the TMLHE gene (TMLHE KO) in mice is expected to limit long-chain acylcarnitine synthesis and thus induce a cardio- and mitochondria-protective phenotype. TMLHE gene deletion in male mice lowered acylcarnitine concentrations in blood and cardiac tissues by up to 85% and decreased fatty acid oxidation by 30% but did not affect muscle and heart function in mice. Metabolome profile analysis revealed increased levels of polyunsaturated fatty acids (PUFAs) and a global shift in fatty acid content from saturated to unsaturated lipids. In the risk area of ischemic hearts in TMLHE KO mouse, the OXPHOS-dependent respiration rate and OXPHOS coupling efficiency were fully preserved. Additionally, the decreased long-chain acylcarnitine synthesis rate in TMLHE KO mice prevented ischaemia-reperfusion-induced ROS production in cardiac mitochondria. This was associated with a 39% smaller infarct size in the TMLHE KO mice. The arrest of the acylcarnitine biosynthesis pathway in TMLHE KO mice prevents ischaemia-reperfusion-induced damage in cardiac mitochondria and decreases infarct size. These results confirm that the decreased accumulation of ROS-increasing fatty acid metabolism intermediates prevents mitochondrial and cardiac damage during ischaemia-reperfusion. [Display omitted] •TMLHE gene deletion is associated with lower acylcarnitine concentrations in plasma and tissues.•Accumulated long-chain acylcarnitines induce ROS production during reperfusion.•I/R-induced mitochondrial ROS production was lower in TMLHE KO mouse hearts.•TMLD is a novel drug target for cardioprotection.
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ISSN:0891-5849
1873-4596
1873-4596
DOI:10.1016/j.freeradbiomed.2021.10.035