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SLC25-family transporters of choline and branched-chain and methylated amino acids regulate mitochondrial protein synthesis

ABSTRACT: Genome-wide knock out screen identified members of the SLC25 family of mitochondrial carrier proteins as important regulators of the rate of de novo mitochondrial protein synthesis. To elucidate this relationship, we generated human cell knockouts for SLC25A25, SLC25A44, SLC25A45, and SLC25A48, which have been shown to exchange ATP and magnesium, branched-chain amino acids, methylated basic amino acids, and choline, respectively. Multiomic and functional analyses identified that these four carriers are crucial for mitochondrial translation, biogenesis and function of the oxidative phosphorylation system, as well as mitochondrial morphology. Thermostability screens showed that SLC25A48 is specifically stabilised by choline and changes in the mitochondrial metabolome and lipidome indicated defects in choline biosynthetic pathways and remodelling of mitochondrial membranes, both consistent with SLC25A48 being a choline transporter. These results highlight the essential roles of specific SLC25 transporters in maintaining mitochondrial structure and function, and show that of mitochondrial translation is sensitive to local concentrations of branched chain amino acids, methylated basic amino acids, ATP, magnesium and choline.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast Epithelium

DISEASE(S): Disease Free

SUBMITTER: Timothy McCubbin

LAB HEAD: Aleksandra Filipovska

PROVIDER: PXD066637 | Pride | 2025-12-19

REPOSITORIES: Pride

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			Action	DRS
	20210902_T2_001.raw	Raw
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	20210902_T2_003.raw	Raw
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	20210902_T2_005.raw	Raw

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Specific SLC25 carriers regulate mitochondrial protein synthesis

Project description:A genome-wide knock out screen identified members of the SLC25 family of mitochondrial carrier proteins as important regulators of the rate of de novo mitochondrial protein synthesis. To elucidate this relationship, we generated human cell knockouts for SLC25A25, SLC25A44, SLC25A45, and SLC25A48, which have been shown to exchange ATP and magnesium, branched-chain amino acids, methylated basic amino acids, and choline, respectively. Multi-omic and functional analyses identified that these four carriers are crucial for mitochondrial translation, biogenesis and function of the oxidative phosphorylation system, as well as mitochondrial morphology. Thermostability screens showed that SLC25A48 is specifically stabilised by choline and changes in the mitochondrial metabolome and lipidome indicated defects in choline biosynthetic pathways and remodelling of mitochondrial membranes, both consistent with SLC25A48 being a choline transporter. These results highlight the essential roles of specific SLC25 transporters in maintaining mitochondrial structure and function and show that of mitochondrial translation is sensitive to local concentrations of branched chain amino acids, methylated basic amino acids, ATP, magnesium, and choline.

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SLC25A45 is required for mitochondrial uptake of methylated basic amino acids and de novo carnitine biosynthesis

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