L-Glutamate enables the EGFR-MEK-ERK-mTFB2 axis to enhance mitochondrial biogenesis in intestinal stem cells

Background: Intestinal stem cells (ISCs) sustain epithelial homeostasis through rapid Mitochondrial Metabolism, however, how they sense nutrient signals to regulate mitochondrial function remains unclear.

Methods: We examined the role of L-glutamate (Glu) in regulating cell mitochondrial biosynthesis using in vivo piglets, ex vivo porcine intestinal organoids (IOs), and in vitro IPEC-J2 cells.

Results: Glu enhanced jejunal development in weaned piglets. Isobaric tags for relative and absolute quantitation (iTRAQ) analysis revealed the significant enrichment of mitochondrial functions and activation of EGFR-MEK-ERK-mTFB2 signaling pathway in the jejunum. In vitro, 5 mM Glu promotes mitochondrial biosynthesis and potentiates the EGFR-MEK-ERK-mTFB2 axis. Whereas inhibition of EGFR with Osimertinib and silencing EGFR abolished these effects in IOs and IPEC-J2 cells. Colocalization and biochemical studies demonstrated interaction between Glu and EGFR in IOs.

Conclusions: Glu promotes mitochondrial biogenesis and ISC expansion by activating the EGFR-MEK-ERK-mTFB2 axis, highlighting a nutrient-sensing mechanism that couples energy availability to ISC function.