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Mitochondrial PEP import controls amino acid catabolism and muscle integrity through SLC25A34

ABSTRACT: Metabolic flexibility enables eukaryotic cells to adapt to stress by dynamically reallocating fuels among distinct metabolite pools. In skeletal muscle, prolonged fasting promotes a shift in substrate utilization from glucose toward amino acids, yet the molecular mechanisms governing this fuel switching remain incompletely defined. Mitochondria are central to this process by coordinating oxidative metabolism and importing/exporting metabolites through inner-membrane transporters, including members of the SLC25 carrier family. Notably, many SLC25 transporters remain “orphan carriers,” with unknown substrates and functions. Here, we identify SLC25A34 as a fasting-inducible orphan mitochondrial carrier that is highly enriched in the slow-twitch skeletal muscles. Muscle-specific Slc25a34 deficiency results in muscle hypertrophy accompanied by myopathic features, implicating SLC25A34 in muscle homeostasis. Additionally, we reconstituted SLC25A34 into proteoliposomes and directly quantified transport activity, revealing that SLC25A34 functions as a phosphoenolpyruvate (PEP) transporter. Together, these results identified SLC25A34 is a PEP transporter that regulates amino acid catabolism and muscle integrity.

ORGANISM(S): Mus musculus

PROVIDER: GSE311513 | GEO | 2026/06/17

REPOSITORIES: GEO

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	GSE311513_TPM_values.csv.gz	Csv
	GSE311513_raw_counts.csv.gz	Csv

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Fasting upregulates the monocarboxylate transporter Mct1 at the rat blood-brain barrier through Ppar δ activation

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Genetic deletion or pharmacologic blockade of the amino acid transporter Slc6a14 in mice suppresses breast cancer induced by Polyoma middle T oncogene

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Fasting response of mouse brain

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Specific SLC25 carriers regulate mitochondrial protein synthesis

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Fasting upregulates the monocarboxylate transporter Mct1 at the rat blood-brain barrier through Ppar d activation

Project description:Fasting is increasingly recognized as a potential therapeutic intervention in the field of neurology and psychiatry. However, its impact upon the blood-brain barrier (BBB), which strictly regulates the cerebral uptake of a wide range of endogenous compounds and drugs, is unknown. In this study we used a combination of in vivo and in vitro experiments to assess the response of the brain endothelium in rats that were fed ad libitum or fasted for one to three days. Fasting did not change the expression of the main drug efflux ATP-binding cassette transporters or P-glycoprotein activity at the BBB but modulated a restrictive set of solute carrier transporters. These included the monocarboxylate transporter Mct1, which is pivotal for the cerebral uptake of ketone bodies and thus for brain adaptation to fasting. Transcriptional profiling of freshly isolated brain endothelial cells showed that Ppar d, a major lipid sensor, was selectively activated in response to fasting. In primary cultured rat brain endothelial cells, pharmacological agonists and free fatty acids selectively activated Ppar d, resulting in the upregulation of Mct1 expression at the transcriptional and protein level. This was confirmed in vivo, by showing that dosing rats with a specific Ppar d antagonist blocked the upregulation of Mct1 expression and activity induced by fasting. Altogether, our study describes for the first time a selective adaptive response of the brain vasculature to fasting and opens new perspectives for the metabolic manipulation of the BBB in the healthy or diseased brain. To further confirm that the Ppar d pathway is active brain endothelial cells, we exposed pc-CECs to GW0742 in the presence or not of GSK0660 for 48 hours and analyzed the cell lysate using non-targeted quantitative proteomics (n=3).

| PXD044587 | JPOST Repository

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