Mitochondrial control of glycerolipid synthesis by a PEP shuttle.

Summary

This mechanistic study identifies SLC25A35 as a mitochondrial phosphoenolpyruvate (PEP) exporter that drives glyceroneogenesis and glycerolipid synthesis in lipogenic cells. Structural/reconstitution assays confirmed PEP transport, and liver-specific inhibition in obese mice alleviated steatosis and improved systemic glucose homeostasis, highlighting a druggable mitochondrial node in NAFLD and type 2 diabetes.

Key Findings

• SLC25A35 mediates pH gradient–dependent mitochondrial PEP efflux, fueling glyceroneogenesis.
• Loss of SLC25A35 in adipocytes reduces conversion of mitochondrial PEP to glycerol-3-phosphate and diminishes glycerolipid synthesis.
• Hepatic inhibition of SLC25A35 in obese mice alleviates steatosis and improves systemic glucose homeostasis.

Clinical Implications

Targeting SLC25A35 or the mitochondrial PEP shuttle could reduce hepatic triglyceride synthesis and improve glycemic control in NAFLD and type 2 diabetes; it supports development of liver-directed inhibitors or nutrient strategies (e.g., modulating the pyruvate-to-PEP bypass).

Limitations

• Preclinical models; human translational efficacy and safety of SLC25A35 inhibition remain untested.
• Specificity and potential compensatory pathways for mitochondrial PEP transport in diverse tissues require clarification.

Future Directions

Define pharmacology and safety of selective SLC25A35 inhibitors; validate pathway activity and biomarkers in human NAFLD/T2D; assess tissue specificity and long-term metabolic/cardiac effects.