MassIVE MSV000098382

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

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Description

Methylated amino acids accumulate upon the degradation of methylated proteins and are implicated in diverse metabolic and signalling pathways. Consequently, disturbed methylated amino acid homeostasis is associated with cardiovascular disease and renal failure. Mitochondria are core processing hubs in conventional amino acid metabolism but how they interact with methylated amino acids is unclear. Here, we reveal that the orphan mitochondrial solute carrier SLC25A45 is required for the mitochondrial uptake of methylated amino acids. SLC25A45 binds with dimethylarginine and trimethyllysine but has no affinity for unmethylated arginine and lysine. A non-synonymous mutation of human SLC25A45 (R285C) stabilises the carrier by limiting its proteolytic degradation by the m-AAA protease and associates with altered methylated amino acids in human plasma. Metabolic tracing of trimethyllysine in cancer cells demonstrates that SLC25A45 drives the biosynthesis of the key metabolite carnitine. Furthermore, depletion of SLC25A45 limits the proliferation and survival of ovarian cancer cells upon glucose deprivation. SLC25A45 is therefore an essential mediator of compartmentalised methylated amino acid metabolism with diverse cellular roles. [doi:10.25345/C5V11VZ6S] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Mitochondria ; solute carriers ; metabolite transport ; carnitine biosynthesis ; DatasetType:Metabolomics

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Principal Investigators:
(in alphabetical order) 		David Sumpton, CRUK Scotland Insititue, United Kingdom
Marilia Meira Dias, CRUK Scotland Insititue, United Kingdom
Thomas MacVicar, CRUK Scotland Insititue, United Kingdom
Submitting User: dsumpton
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