Effects of SLC6A8 mutation-induced creatine deficiency on cellular function in fibroblasts

Area of Science:

• Biochemistry
• Cell Biology
• Genetics

Background:

• Mutations in SLC6A8 cause creatine transporter deficiency (CTD), a condition leading to cerebral creatine deficiency syndromes.
• The precise cellular consequences of creatine transporter (CRT) loss, particularly from specific mutations, remain incompletely understood.

Purpose of the Study:

• To investigate the cellular impact of the G561R mutation in the creatine transporter (CRT).
• To elucidate the molecular and functional deficits caused by CRT loss in fibroblasts.

Main Methods:

• Fibroblast analysis using proteomics and functional assays.
• Assessment of intracellular creatine levels, energy metabolism (ATP/ADP ratios), mitochondrial function, oxidative stress, and amino acid transporter activity.

Main Results:

• The G561R mutation caused over 90% intracellular creatine reduction, severely impairing energy metabolism (low ATP, high ADP/ATP).
• Proteomics identified significant alterations in mitochondrial and extracellular vesicle pathways, indicating impaired oxidative phosphorylation and reduced respiratory capacity.
• Elevated oxidative stress and altered amino acid transporter activity were observed; protein misfolding exacerbated these deficits.

Conclusions:

• The CRT-G561R mutation induces significant energy metabolic reprogramming, mitochondrial dysfunction, and cellular stress.
• These findings enhance understanding of creatine transporter deficiency pathogenesis.
• The study suggests potential therapeutic targets for CTD.