Glyceroneogenesis Has a New PEP in Its Step(s)

Why It Matters

By exposing a new control point for lipid metabolism, the finding opens avenues for therapeutic strategies against obesity, diabetes, and metabolic‑associated steatotic liver disease (MASLD).

Key Takeaways

• SLC25A35 identified as mitochondrial phosphoenolpyruvate exporter
• Export enables glyceroneogenesis in adipocytes
• Loss of SLC25A35 impairs lipid handling in fatty liver models
• Mitochondrial PEP flux now linked to metabolic disease risk
• Targeting SLC25A35 could treat obesity and MASLD

Pulse Analysis

The identification of SLC25A35 as a dedicated mitochondrial phosphoenolpyruvate (PEP) exporter reshapes our understanding of intracellular carbon routing. Historically, mitochondria were viewed primarily as powerhouses that feed the cytosol with ATP and TCA‑cycle intermediates. This new transporter creates a direct conduit for PEP, a glycolytic intermediate, to exit the matrix and enter the glyceroneogenic pathway. By bridging mitochondrial output with cytosolic lipid synthesis, SLC25A35 adds a layer of regulation that can fine‑tune triglyceride formation in response to nutritional cues.

In adipose tissue, glyceroneogenesis supplies glycerol‑3‑phosphate for re‑esterifying free fatty acids, a process essential for maintaining lipid homeostasis. The study demonstrates that mice lacking SLC25A35 exhibit reduced glyceroneogenic flux, leading to elevated circulating fatty acids and accelerated accumulation of triglycerides in the liver. This mechanistic link explains why mitochondrial PEP production, previously considered a by‑product of gluconeogenesis, now appears critical for preventing hepatic steatosis, especially under high‑fat dietary conditions.

Clinically, the SLC25A35‑PEP axis presents a promising target for metabolic disease intervention. Pharmacologic activation or gene‑therapy‑based enhancement of this transporter could boost glyceroneogenesis, thereby improving lipid clearance and mitigating the progression of MASLD and obesity‑related complications. Moreover, the discovery invites broader investigation into other mitochondrial metabolite shuttles that may influence systemic metabolism, underscoring the importance of organelle‑specific transporters in drug discovery pipelines.