Fouché Belinda R, Lindeque Zander, van der Westhuizen Francois, Venter Marianne, van der Sluis Rencia
Biomedical and Molecular Metabolism Research (BioMMet), North-West University, Potchefstroom Campus, Private Bag X6001, Potchefstroom, 2520, South Africa.
Biomedical and Molecular Metabolism Research (BioMMet), North-West University, Potchefstroom Campus, Private Bag X6001, Potchefstroom, 2520, South Africa.
Biochem Biophys Res Commun. 2025 Sep 1;777:152278. doi: 10.1016/j.bbrc.2025.152278. Epub 2025 Jul 1.
Leigh syndrome (LS), a primary mitochondrial disease frequently caused by complex I (CI) deficiency, has been associated with hepatic dysfunction and impaired metabolic homeostasis. Despite this, the impact of mitochondrial dysfunction on hepatic xenobiotic detoxification pathways remains poorly understood. This study investigated the glycine conjugation pathway-central to the metabolism of dietary xenobiotics such as benzoate, salicylate, and medium-chain fatty acids (MCFAs)-in a whole-body Ndufs4 knockout (Ndufs4) mouse model of LS. Transcriptomic analysis revealed a significant downregulation of the xenobiotic/medium chain fatty acid: CoA ligases (Acsm1 and Acsm2) and glycine N-acyltransferase (Glyat) in the livers of Ndufs4 mice, suggesting impaired activation and conjugation of xenobiotics. This was corroborated by reduced GLYAT (EC2.3.1.13) enzymatic activity and a marked decrease in hepatic hexanoylglycine levels. These findings imply that CI deficiency attenuates glycine conjugation capacity, potentially compromising the liver's ability to metabolise xenobiotic and dietary substrates. Given the role of glycine conjugation in detoxification, our data highlight a metabolic vulnerability in LS that may influence dietary and pharmacological interventions. Adjusting dietary intake of conjugation substrates may therefore be crucial in the clinical management of mitochondrial disease.
Leigh综合征（LS）是一种常见的原发性线粒体疾病，常由复合体I（CI）缺乏引起，与肝功能障碍和代谢稳态受损有关。尽管如此，线粒体功能障碍对肝脏外源性物质解毒途径的影响仍知之甚少。本研究在LS的全身Ndufs4基因敲除（Ndufs4）小鼠模型中，研究了甘氨酸结合途径——饮食中外源性物质如苯甲酸盐、水杨酸盐和中链脂肪酸（MCFAs）代谢的核心途径。转录组分析显示，Ndufs4小鼠肝脏中外源性物质/中链脂肪酸：辅酶A连接酶（Acsm1和Acsm2）和甘氨酸N-酰基转移酶（Glyat）显著下调，提示外源性物质的活化和结合受损。GLYAT（EC2.3.1.13）酶活性降低和肝脏己酰甘氨酸水平显著下降证实了这一点。这些发现表明，CI缺乏会削弱甘氨酸结合能力，可能损害肝脏代谢外源性物质和饮食底物的能力。鉴于甘氨酸结合在解毒中的作用，我们的数据突出了LS中的一种代谢脆弱性，可能会影响饮食和药物干预。因此，调整结合底物的饮食摄入量可能在线粒体疾病的临床管理中至关重要。
