SLC25A45 is required for mitochondrial uptake of methylated basic amino acids and de novo carnitine biosynthesis (Part 1 = Proteome Analysis)

Methylated amino acids accumulate upon the degradation of methylated proteins and are implicated in diverse metabolic and signalling pathways. Dimethylarginine inhibits nitric oxide synthase while trimethyllysine is metabolised in a compartmentalised manner to produce the amino acid derivative carnitine. Consequently, disturbed methylated amino acid homeostasis is associated with various disorders including cardiovascular disease and renal failure. Mitochondria are core processing hubs in conventional amino acid metabolism but how they interact with methylated amino acids is unclear. Here, we reveal that the orphan mitochondrial solute carrier SLC25A45 is required for the mitochondrial uptake of dimethylarginine and trimethyllysine. Characterisation of SLC25A45 identified a non-synonymous mutation of SLC25A45 near its C-terminus (R285C) that impacts solute carrier stability and associates with altered plasma methylated amino acid levels and cardiac alterations in men. Metabolic tracing of trimethyllysine reveals that SLC25A45 is essential for the de novo biosynthesis of carnitine. Suppression of SLC25A45 reduces intracellular acetylcarnitine levels and limits histone acetylation in carnitine-synthesising ovarian cancer cells. We propose that SLC25A45 is an essential mediator of compartmentalised methylated amino acid metabolism with diverse cellular roles that include epigenetic control.

甲基化氨基酸在甲基化蛋白质降解过程中积累，并参与多种代谢与信号通路。二甲基精氨酸可抑制一氧化氮合酶，而三甲基赖氨酸则以区室化方式代谢生成氨基酸衍生物肉碱。因此，甲基化氨基酸稳态失衡与多种疾病相关，包括心血管疾病与肾衰竭。线粒体是常规氨基酸代谢的核心加工枢纽，但线粒体与甲基化氨基酸的相互作用机制尚不清楚。本研究揭示孤儿线粒体溶质载体SLC25A45是二甲基精氨酸与三甲基赖氨酸线粒体摄取过程所必需的蛋白。对SLC25A45的表征研究发现，其C端附近存在一处非同义突变（R285C），该突变会影响溶质载体的稳定性，并与男性个体血浆甲基化氨基酸水平改变及心脏异常相关。三甲基赖氨酸的代谢示踪实验表明，SLC25A45对于肉碱的从头生物合成至关重要。抑制SLC25A45的表达会降低合成肉碱的卵巢癌细胞内的乙酰肉碱水平，并限制其组蛋白乙酰化过程。我们提出，SLC25A45是区室化甲基化氨基酸代谢的关键介导因子，其参与包括表观遗传调控在内的多种细胞功能。