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Mitochondrial choline import regulates purine nucleotide pools via SLC25A48.

bioRxiv : the preprint server for biology | 2024

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.

Pubmed ID: 38260464 RIS Download

Associated grants

  • Agency: NIDDK NIH HHS, United States
    Id: DP1 DK126160
  • Agency: NIDDK NIH HHS, United States
    Id: P30 DK135043
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK097441
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK125283

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