| First Author | Liepinsh E | Year | 2021 |
| Journal | Free Radic Biol Med | Volume | 177 |
| Pages | 370-380 | PubMed ID | 34728372 |
| Mgi Jnum | J:341247 | Mgi Id | MGI:6854474 |
| Doi | 10.1016/j.freeradbiomed.2021.10.035 | Citation | Liepinsh E, et al. (2021) Low cardiac content of long-chain acylcarnitines in TMLHE knockout mice prevents ischaemia-reperfusion-induced mitochondrial and cardiac damage. Free Radic Biol Med 177:370-380 |
| abstractText | Increased tissue content of long-chain acylcarnitines may induce mitochondrial and cardiac damage by stimulating ROS production. N(6)-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. |
