A creatine efflux transporter in oligodendrocytes.

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Creatine is vital for ATP regeneration in high-energy-demand cells, and its deficiency causes neurodevelopmental issues.
• Oligodendrocytes synthesize creatine in the brain to supply neurons, with uptake mediated by SLC6A8, but release mechanisms remained unknown.
• Understanding creatine release is critical for brain energy metabolism and preventing neurological disorders.

Purpose of the Study:

• To investigate the function of the highly conserved transporter SLC22A15 in creatine release.
• To determine if SLC22A15 mediates the controlled release of creatine from producing cells, particularly oligodendrocytes.
• To elucidate the regulatory mechanisms and cellular localization of SLC22A15 in creatine transport.

Main Methods:

• Heterologous expression of human and rat SLC22A15 in 293 cells.
• Analysis of substrate release using mass spectrometry.
• Examination of SLC22A15 mRNA expression profiles in human and mouse tissues and single-cell RNA sequencing data.

Main Results:

• SLC22A15 was identified as a transporter of various zwitterions, with creatine efflux significantly exceeding other substrates.
• SLC22A15 is regulated and inactive by default, preventing uncontrolled creatine loss, and can be triggered by external substrates for one-to-one exchange.
• SLC22A15 expression is highest in oligodendrocytes and macrophages, correlating with high intracellular creatine synthesis enzyme (AGAT and GAMT) levels, unlike in proximal tubular cells and hepatocytes.

Conclusions:

• SLC22A15 is established as the pivotal transporter for regulated creatine release from oligodendrocytes.
• This finding fills a critical knowledge gap in brain creatine metabolism and transport.
• The regulated release mechanism mediated by SLC22A15 is crucial for maintaining neuronal energy homeostasis and preventing neurodevelopmental impairments.