Glutamine-Dependent Slc25a39-Nrf2 Axis Couples Mitochondrial Dynamics with Metabolic Reprogramming to Establish...

Area of Science:

• Cellular Biology
• Muscle Regeneration
• Metabolic Regulation

Background:

• Myogenic commitment is crucial for skeletal muscle regeneration.
• Amino acids, particularly glutamine, influence this process by linking metabolism and gene expression.
• Myoblasts must sense nutrient availability for proper progression.

Purpose of the Study:

• Investigate the molecular consequences of glutamine withdrawal on myoblasts.
• Identify the cellular mechanisms and states induced by glutamine limitation.
• Determine the role of glutamine sensing in myogenic commitment and differentiation.

Main Methods:

• Acute glutamine withdrawal experiments in myoblasts.
• Analysis of metabolic pathways (glycolysis, oxidation).
• Mitochondrial morphology and function assessment (fission, depolarization).
• Transcriptomic profiling (gene expression analysis).
• Investigation of redox balance and glutathione pathways.

Main Results:

• Glutamine oxidation supports glycolysis, mitochondrial fission, and redox balance for myogenic commitment.
• Glutamine withdrawal triggers a reductive shift, mitochondrial elongation, and growth arrest.
• A reversible Poised Metabolic Arrest (PMA) state is induced, characterized by specific gene expression changes.
• PMA is mediated by Nrf2-dependent glutathione biosynthesis and Slc25a39 upregulation.
• Slc25a39 and mitochondrial glutathione are critical for maintaining PMA and differentiation potential.

Conclusions:

• Glutamine availability is sensed by myoblasts to regulate progression toward myogenic commitment.
• Poised Metabolic Arrest (PMA) is a glutamine-dependent checkpoint preserving differentiation capacity.
• A Slc25a39-Nrf2 redox axis couples glutamine sensing to mitochondrial and metabolic adaptations for muscle regeneration.