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Specific SLC25 carriers regulate mitochondrial protein synthesis

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE304693 | GEO | 2025/12/18

REPOSITORIES: GEO

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

Project description: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.

2025-12-19 | PXD066637 | Pride

Impact of Preoperative Oral Branched-chain Amino Acids on Reducing Postoperative Insulin Resistance.

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Branched Chain Amino Acids (BCAA) Modulate Metabolic Inflammation

Project description:Branched Chain Amino Acids (BCAA) Modulate Metabolic Inflammation

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Project description:Atxn2-Knock-Out mice show branched-chain amino acids and fatty acids pathway alterations

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Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy

Project description:Autism is present in 1% of the population, yet treatments are extremely limited. We identified homozygous inactivating mutations in the BCKDK gene in families presenting with autism and epilepsy. The encoded branched chain ketoacid dehydrogenase kinase protein is responsible for phosphorylation-mediated inactivation of the E1-alpha subunit of branched chain ketoacid dehydrogenase, itself mutated in Maple Syrup Urine Disease (MSUD). Patients with homozygous BCKDK mutations display reductions in BCKDK mRNA and protein, E1-alpha phosphorylation and serum branched chain amino acids (BCAAs). Bckdk knockout mice show abnormal brain amino acids profiles and neurobehavioral defects, which are largely corrected by dietary BCAA supplementation. Thus autism presenting with epilepsy due to BCKDK mutations represent a new and potentially treatable disease.

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2020-11-23 | GSE148701 | GEO

Codon-specific ribosome stalling reshapes translational dynamics during branched-chain amino acid starvation

Project description:Background: Cells regulate protein synthesis in response to fluctuating nutrient availability through mechanisms that affect both translation initiation and elongation. Branched-chain amino acids, leucine, isoleucine, and valine, are essential nutrients. However, how their depletion affects translation remains largely unclear. Here, we investigate the immediate effects of single, double, and triple branched-chain amino acid deprivation on translational dynamics in NIH3T3 cells using RNA-seq and ribosome profiling. Results: All starvation conditions increased ribosome dwell times, with pronounced stalling at all valine codons during valine and triple starvation, whereas leucine and isoleucine starvation produced milder, codon-specific effects. Notably, stalling under isoleucine deprivation largely decreased under triple starvation. Positional enrichment of valine codons near the 5' end and downstream isoleucine codons potentially contributes to these patterns, suggesting a possible elongation bottleneck that influences translational responses under branched-chain amino acid starvation. The presence of multiple valine stalling sites was associated with decreased protein levels. Finally, codon-specific dwell time changes correlated strongly with patterns of tRNA isoacceptor charging. Conclusions: Together, these findings suggest that differential ribosome stalling under branched-chain amino acid starvation reflects a balance between amino acid supply, tRNA charging dynamics, codon position, and stress-response signaling.

2025-09-02 | GSE291652 | GEO

Codon-specific ribosome stalling reshapes translational dynamics during branched-chain amino acid starvation

Project description:Background Cells regulate protein synthesis in response to fluctuating nutrient availability through mechanisms that affect both translation initiation and elongation. Branched-chain amino acids, leucine, isoleucine, and valine, are essential nutrients. However, how their depletion affects translation remains largely unclear. Here, we investigate the immediate effects of single, double, and triple branched-chain amino acid deprivation on translational dynamics in NIH3T3 cells using RNA-seq and ribosome profiling. Results All starvation conditions increased ribosome dwell times, with pronounced stalling at all valine codons during valine and triple starvation, whereas leucine and isoleucine starvation produced milder, codon-specific effects. Notably, stalling under isoleucine deprivation largely decreased under triple starvation. Positional enrichment of valine codons near the 5′ end and downstream isoleucine codons potentially contributes to these patterns, suggesting a possible elongation bottleneck that influences translational responses under branched-chain amino acid starvation. The presence of multiple valine stalling sites was associated with decreased protein levels. Finally, codon-specific dwell time changes correlated strongly with patterns of tRNA isoacceptor charging. Conclusions Together, these findings suggest that differential ribosome stalling under branched-chain amino acid starvation reflects a balance between amino acid supply, tRNA charging dynamics, codon position, and stress-response signaling.

2025-09-02 | GSE291653 | GEO

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