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Effects of SLC6A8 mutation-induced creatine deficiency on cellular function in fibroblasts
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Effects of SLC6A8 mutation-induced creatine deficiency on cellular function in fibroblasts
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Effects of SLC6A8 mutation-induced creatine deficiency on cellular function in fibroblasts
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Journal Article
Effects of SLC6A8 mutation-induced creatine deficiency on cellular function in fibroblasts
2025
Overview
Creatine transporter deficiency (CTD) caused by mutations in
SLC6A8
encoding the creatine transporter (CRT), leads to cerebral creatine deficiency syndromes; however, the cellular impact of CRT loss remains unclear. In this study, we investigated the consequences of the G561R mutation by examining fibroblasts using proteomics and functional assays. We observed severe intracellular creatine deficiency (> 90% reduction), leading to impaired energy metabolism (low ATP and high ADP/ATP). Proteomic analysis revealed significant alterations in the mitochondrial and extracellular vesicle pathways. Our investigation revealed impaired mitochondrial oxidative phosphorylation, reduced spare respiratory capacity, elevated oxidative stress, and significant alterations in amino acid transporter activity. Protein misfolding associated with G561R exacerbated these deficits compared to the deletion model. These findings elucidate the key pathological mechanisms induced by the CRT-G561R mutation—including energy metabolic reprogramming, mitochondrial dysfunction, and cellular stress—which significantly contribute to our understanding of the pathogenesis of creatine transporter deficiency and suggest potential therapeutic targets.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 631/80
/ 692/699
/ Brain Diseases, Metabolic, Inborn - genetics
/ Brain Diseases, Metabolic, Inborn - metabolism
/ Creatine
/ Energy
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Muscle Weakness - metabolism
/ Mutation
/ Nerve Tissue Proteins - genetics
/ Nerve Tissue Proteins - metabolism
/ Plasma
/ Plasma Membrane Neurotransmitter Transport Proteins - deficiency
/ Plasma Membrane Neurotransmitter Transport Proteins - genetics
/ Plasma Membrane Neurotransmitter Transport Proteins - metabolism
/ Proteins
/ Science
/ SLC6A8
/ X-Linked Intellectual Disability - genetics
