栄養素の体内移動の可視化でがん治療戦略を最適化(Mapping how nutrients move through the body to treat cancer)

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2025-06-11 ロックフェラー大学

ロックフェラー大学の研究で、栄養素が体内の細胞に取り込まれる経路を網羅的にマッピング。特にがん細胞はアスパラギンやグルタチオンの輸送を強化し、成長や転移に関与することが判明しました。輸送体を標的とすることでがんの拡大を抑制できる可能性が示され、栄養素の適正使用やがん治療における新戦略につながる成果です。

<関連情報>

ミトコンドリアグルタチオンホメオスタシスの自己調節性制御 Autoregulatory control of mitochondrial glutathione homeostasis

Yuyang Liu, Shanshan Liu, Anju Tomar, Frederick S. Yen, Gokhan Unlu, Nathalie Ropek, Ross A. Weber, Ying Wang, Artem Khan, […] , and Kıvanç Birsoy
Science  Published:2 Nov 2023
DOI:https://doi.org/10.1126/science.adf4154

Editor’s summary

Glutathione (GSH) has important roles as an antioxidant and in iron homeostasis and other cellular functions. It is transported into mitochondria by the transporter protein SLC25A39, and the abundance of SLC25A39 increases if concentrations of GSH in mitochondria are low, providing a feedback control to maintain GSH concentrations. Liu et al. report that the abundance of SLC25A39 is regulated by its association with a protease, AFG3L2. They propose that when mitochondrial GSH concentrations are low, binding of AFG3L2 to SLC25A3p (and thus its degradation) is prevented because an iron–sulfur cluster competitively binds to SLC25A30. Such a mechanism could help to coordinate iron homeostasis and maintenance of GSH concentrations in the mitochondria. —L. Bryan Ray

Abstract

Mitochondria must maintain adequate amounts of metabolites for protective and biosynthetic functions. However, how mitochondria sense the abundance of metabolites and regulate metabolic homeostasis is not well understood. In this work, we focused on glutathione (GSH), a critical redox metabolite in mitochondria, and identified a feedback mechanism that controls its abundance through the mitochondrial GSH transporter, SLC25A39. Under physiological conditions, SLC25A39 is rapidly degraded by mitochondrial protease AFG3L2. Depletion of GSH dissociates AFG3L2 from SLC25A39, causing a compensatory increase in mitochondrial GSH uptake. Genetic and proteomic analyses identified a putative iron-sulfur cluster in the matrix-facing loop of SLC25A39 as essential for this regulation, coupling mitochondrial iron homeostasis to GSH import. Altogether, our work revealed a paradigm for the autoregulatory control of metabolic homeostasis in organelles.

統合的遺伝子解析により、FLVCR1が哺乳類の血漿膜コリン輸送体であることが明らかになった Integrative genetic analysis identifies FLVCR1 as a plasma-membrane choline transporter in mammals

Timothy C. Kenny ∙ Artem Khan ∙ Yeeun Son ∙ … ∙ Hanan Alwaseem ∙ Richard K. Hite ∙ Kıvanç Birsoy
Cell Metabolism  Published:April 25, 2023
DOI:https://doi.org/10.1016/j.cmet.2023.04.003

Graphical abstract

栄養素の体内移動の可視化でがん治療戦略を最適化(Mapping how nutrients move through the body to treat cancer)

Highlights

•Identification of metabolite transporter associations from GWAS of serum metabolites

•FLVCR1 is required for choline uptake and metabolism

•Loss of FLVCR1 impairs mitochondrial function leading to the activation of ISRmt

•Flvcr1-mediated choline transport is necessary for murine embryogenesis

Summary

Genome-wide association studies (GWASs) of serum metabolites have the potential to uncover genes that influence human metabolism. Here, we combined an integrative genetic analysis that associates serum metabolites to membrane transporters with a coessentiality map of metabolic genes. This analysis revealed a connection between feline leukemia virus subgroup C cellular receptor 1 (FLVCR1) and phosphocholine, a downstream metabolite of choline metabolism. Loss of FLVCR1 in human cells strongly impairs choline metabolism due to the inhibition of choline import. Consistently, CRISPR-based genetic screens identified phospholipid synthesis and salvage machinery as synthetic lethal with FLVCR1 loss. Cells and mice lacking FLVCR1 exhibit structural defects in mitochondria and upregulate integrated stress response (ISR) through heme-regulated inhibitor (HRI) kinase. Finally, Flvcr1 knockout mice are embryonic lethal, which is partially rescued by choline supplementation. Altogether, our findings propose FLVCR1 as a major choline transporter in mammals and provide a platform to discover substrates for unknown metabolite transporters.

生物化学工学
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