美国霍华德休斯医学研究所Shingo Kajimura团队在研究中取得进展。他们提出了SLC25A48控制线粒体胆碱的输入和代谢。这一研究成果于2024年8月6日发表在国际顶尖学术期刊《细胞—代谢》上。

小组报道了SLC25A48，一个以前未被表征的线粒体内膜载体蛋白，控制线粒体胆碱运输和胆碱衍生甲基供体的合成。研究组发现SLC25A48是褐色脂肪产热、线粒体呼吸和线粒体膜完整性所必需的。通过SLC25A48摄取胆碱进入线粒体基质促进了甜菜碱和嘌呤核苷酸的合成，而SLC25A48的缺失导致线粒体活性氧的产生增加和线粒体脂质失衡。

值得注意的是，携带SLC25A48基因单核苷酸多态性的人类细胞和缺乏SLC25A48基因的癌细胞表现出线粒体胆碱输入减少、氧化应激增加和细胞增殖受损。总之，本研究表明SLC25A48调节线粒体胆碱分解代谢、生物能量学和细胞存活。

据介绍，胆碱是生物合成磷脂、神经递质和单碳代谢的必需营养素，其关键步骤是进入线粒体。然而，潜在的机制和生物学意义仍然知之甚少。

附：英文原文

Title: SLC25A48 controls mitochondrial choline import and metabolism

Author: Anthony R.P. Verkerke, Xu Shi, Mark Li, Yusuke Higuchi, Tadashi Yamamuro, Daisuke Katoh, Hiroshi Nishida, Christopher Auger, Ichitaro Abe, Robert E. Gerszten, Shingo Kajimura

Issue&Volume: 2024-08-06

Abstract: Choline is an essential nutrient for the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism with a critical step being its import into mitochondria. However, the underlying mechanisms and biological significance remain poorly understood. Here, we report that SLC25A48, a previously uncharacterized mitochondrial inner-membrane carrier protein, controls mitochondrial choline transport and the synthesis of choline-derived methyl donors. We found that SLC25A48 was required for brown fat thermogenesis, mitochondrial respiration, and mitochondrial membrane integrity. Choline uptake into the mitochondrial matrix via SLC25A48 facilitated the synthesis of betaine and purine nucleotides, whereas loss of SLC25A48 resulted in increased production of mitochondrial reactive oxygen species and imbalanced mitochondrial lipids. Notably, human cells carrying a single nucleotide polymorphism on the SLC25A48 gene and cancer cells lacking SLC25A48 exhibited decreased mitochondrial choline import, increased oxidative stress, and impaired cell proliferation. Together, this study demonstrates that SLC25A48 regulates mitochondrial choline catabolism, bioenergetics, and cell survival.

DOI: 10.1016/j.cmet.2024.07.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00281-X