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bioRxiv · 10.1101/2023.12.31.573776

Mitochondrial choline import regulates purine nucleotide pools via SLC25A48

Verkerke, A. R. P.·Shi, X.·Abe, I.·Gerszten, R. E.·Kajimura, S.
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Abstract

Choline is an essential nutrient for cellular metabolism, including the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism. A critical step of choline catabolism is the mitochondrial import and synthesis of chorine-derived methyl donors, such as betaine. However, the underlying mechanisms and the biological significance of mitochondrial choline catabolism remain insufficiently understood. Here, we report that a mitochondrial inner-membrane protein SLC25A48 controls mitochondrial choline transport and catabolism in vivo. We demonstrate that SLC25A48 is highly expressed in brown adipose tissue and required for whole-body cold tolerance, thermogenesis, and mitochondrial respiration. Mechanistically, choline uptake into the mitochondrial matrix via SLC25A48 facilitates betaine synthesis and one-carbon metabolism. Importantly, cells lacking SLC25A48 exhibited reduced synthesis of purine nucleotides and failed to initiate the G1-to-S phase transition, thereby leading to cell death. Taken together, the present study identified SLC25A48 as a mitochondrial carrier that mediates choline import and plays a critical role in mitochondrial respiratory capacity, purine nucleotide synthesis, and cell survival. Key pointsO_LISLC25A48 is required for mitochondrial choline uptake. C_LIO_LIMitochondrial choline uptake regulates one-carbon contribution to purine nucleotide synthesis. C_LIO_LIBrown fat thermogenesis requires mitochondrial choline catabolism for respiratory capacity. C_LIO_LICancer cells require mitochondrial choline uptake for cell survival. C_LI

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Verkerke, A. R. P., Shi, X., Abe, I., Gerszten, R. E., Kajimura, S.. 2024-01-01. Mitochondrial choline import regulates purine nucleotide pools via SLC25A48. https://doi.org/10.1101/2023.12.31.573776

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