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SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth

ABSTRACT: Taurine plays a crucial role in mitochondrial tRNA modification essential for mitochondrial translation. Mammalian cells obtain taurine through plasma membrane transporter SLC6A6-mediated uptake exogenously or cytosolic biosynthesis. However, it remains unclear how taurine enters mitochondria and impacts cellular metabolism. Here we show that SLC6A6 but not exogenous taurine is essential for mitochondrial metabolism and cancer cell growth. We discover that SLC6A6 also localizes to mitochondria and imports taurine for mitochondrial tRNA modification. SLC6A6 deficiency specifically reduces mitochondrial taurine abundance and abrogates mitochondrial translation and cell proliferation. Importantly, Protein kinase A dictates SLC6A6 subcellular localization by promoting plasma membrane while inhibiting mitochondrial localization. Furthermore, we show that NFAT5 is a critical regulator of mitochondrial function through SLC6A6, and targeting the NFAT5-SLC6A6 axis significantly limits mitochondrial translation and tumour growth. Together, these findings suggest that SLC6A6 is a mitochondrial taurine transporter and an exploitable metabolic dependency of cancer.

ORGANISM(S): Homo Sapiens

SUBMITTER: Fuming Li

PROVIDER: PXD071408 | iProX | Sat Nov 29 00:00:00 GMT 2025

REPOSITORIES: iProX

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SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.

Li Liucheng L You Jianwei J Chai Zi-Qing ZQ Li Xueshan X Cai Xinlei X Wang Lin L Yang Fang F Zhu Lingzhi L Mi Wen W Xia Xinyi X Yan Haohang H Li Fei F Wang Juan J Zhao Tong-Jin TJ Chen Ligong L Ji Hongbin H Liu Pingyu P Zhou Xiao-Long XL Chen Li L Li Fuming F

Nature metabolism 20260206 3

Taurine plays a crucial role in mitochondrial translation. Mammalian cells obtain taurine via exogenous uptake mediated by the plasma membrane transporter SLC6A6 or via cytosolic biosynthesis. However, it remains unclear how taurine enters mitochondria and impacts cellular metabolism. Here we show that SLC6A6, but not exogenous taurine, is essential for mitochondrial metabolism and cancer cell growth. We discover that SLC6A6 also localizes to mitochondria and imports taurine for mitochondrial tr ...[more]

PMID: 41652173

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Project description:Background: Metabolic dysregulation has been implicated in bronchopulmonary dysplasia development. Taurine is an essential amino acid for neonates and is critically involved in glucose and fatty acid metabolism. Neonatal tissue obtains taurine mainly through the taurine transporter. The biological role of taurine in neonatal lung development has never been explored. As glucose metabolism mechanistically modulates angiogenesis and angiogenesis is the central player for neonatal lung development, we hypothesize that taurine depletion contributes to bronchopulmonary dysplasia development. Results: Although most genes and proteins for oxidative phosphorylation were enriched in hyperoxia pup lungs, the complex-1 activity decreased. The decrease in taurine-dependent complex-1 core subunits, ND5 and ND6, in hyperoxia lungs reasonably explained the discrepancy. Metabolomics analysis demonstrated decreased lung taurine with increased blood taurine of hyperoxia pups, compatible with the decreased taurine transporter expression. Decreased glycosylation and increased degradation explained the decreased taurine transporter expression. The results of the complementary study using tunicamycin and tauroursodeoxycholic acid studies supported that endoplasmic reticulum stress contributes to decreased taurine transporter expression in hyperoxia lungs. The effect of taurine treatment on reducing endoplasmic reticulum stress, increasing ND5 and ND6 expression, angiogenesis, and, most importantly, the alveolar formation is beneficial to hyperoxia rat pups. Conclusion: Hyperoxia exposure causes endoplasmic reticulum stress, increases taurine transporter degradation, and leads to taurine depletion in the neonatal lungs with subsequent metabolic dysregulation, resulting in poor alveolar formation of the neonatal lungs. We provide evidence of the never-being-reported protective role of taurine in neonatal lung development. The fact that taurine attenuates the severity of bronchopulmonary dysplasia by reducing hyperoxia-induced endoplasmic reticulum stress and mitochondrial dysfunction indicates its therapeutic potential for treating bronchopulmonary dysplasia.

Project description:Taurine ameliorates changes occurring in newborn skeletal muscle as a result of gestational protein restriction in C57BL/6 mice, but taurine supplementation effects may be exaggerated in C57BL/6 mice due to their inherent excessive taurinuria. We examined if maternal taurine supplementation could ameliorate changes in gene expression levels, properties of mitochondria, myogenesis, and nutrient transport and sensing, in male newborn skeletal muscle caused by a maternal low protein (LP) diet in Wistar rats. LP diet resulted in an 11% non-significant decrease in birth weight, which was not rescued by taurine supplementation (LP-Tau). LP-Tau offspring had signifi-cantly lower birth weight compared to controls. Gene expression profiling revealed 895 significantly changed genes, mainly an LP-induced down-regulation of genes involved in protein translation. Taurine fully or partially rescued 32% of these changes, but with no distinct pattern as to which genes were rescued. Skeletal muscle taurine content in LP-Tau offspring was increased, but no changes in mRNA levels of the taurine synthesis pathway were observed. Taurine transporter mRNA levels, but not protein levels, were increased by LP diet. Nutrient sensing pathways were largely unaffected in LP or LP-Tau groups, although taurine supplementation caused an unexpected decrease in total Akt and AMPK protein levels. PAT4 amino acid transporter mRNA was increased by LP, and normalized by taurine supplementation. In conclusion, gestational protein restriction in rats decreased genes involved in protein translation in newborn skeletal muscle and led to changes in nutrient transporters. Taurine partly rescued these changes, hence underscoring the im-portance of taurine in development. We used microarrays to detail changes in global programme of gene expression in newborn offspring skeletal muscle brains from rats subjected to either a control diet, a low protein diet or a low protein diet + taurine supplementation

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SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth

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SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.

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