What question did this study set out to answer?

To explore the role of MPST in regulating mitochondrial metabolism and epithelial differentiation in neonatal airway cells.

March 30, 2026Open Access

3-Mercaptopyruvate Sulfurtransferase (MPST) Regulates Mitochondrial Metabolism and Epithelial Differentiation in Neonatal Patient-derived Airway Cells

Key Points

To explore the role of MPST in regulating mitochondrial metabolism and epithelial differentiation in neonatal airway cells.
Used neonatal patient-derived tracheal airway epithelial cells in a 3D air-liquid interface model.
Applied RNA interference to knock down MPST during air-liquid interface differentiation.
Conducted metabolic flux analysis to assess mitochondrial respiration and glycolysis.
Hyperoxia reduced MPST protein abundance in airway cells.
MPST loss led to early transcriptomic shifts in mitochondrial pathways and reduced ciliated cells.
Observed decreased mitochondrial respiration without a compensatory increase in glycolysis.

Abstract

Early-life airway epithelial development relies on tightly coordinated mitochondrial metabolic programs, yet the pathways that govern normal epithelial maturation during this vulnerable developmental window remain poorly defined. Hyperoxia disrupts airway epithelial maturation, contributing to lung injury and airway remodeling in infants with bronchopulmonary dysplasia (BPD), underscoring the need to identify mitochondrial pathways that regulate early epithelial differentiation. 3-Mercaptopyruvate sulfurtransferase (MPST), a mitochondrial sulfur metabolism enzyme, supports mitochondrial metabolic and bioenergetic function, but its role in human airway epithelial development is unknown. In this study, we used neonatal patient-derived tracheal airway epithelial cells (nTAECs) in a three-dimensional air-liquid interface (ALI) model to show that hyperoxia reduces MPST protein abundance. To determine how MPST loss alters early epithelial differentiation and metabolic homeostasis we used RNAi to knock down MPST during ALI differentiation. MPST loss in nTAECs induced early (ALI day 3) transcriptomic shifts involving mitochondrial metabolic pathways, epithelial differentiation programs, and stress-response signature corresponding with decreased ciliated cell numbers during mid-differentiation phase (ALI day 7). Metabolic flux analysis revealed significantly reduced mitochondrial respiration without compensatory increase in glycolysis, indicative of disrupted metabolic flexibility. Together, these data show that MPST is essential for maintaining mitochondrial metabolic integrity necessary for normal airway epithelial development. Loss of MPST creates a developmental vulnerability that may contribute to hyperoxia-induced airway injury in neonates. Targeting MPST-dependent pathways could represent a new strategy to preserve airway health in infants at risk for BPD airway remodeling.

3-Mercaptopyruvate Sulfurtransferase (MPST) Regulates Mitochondrial Metabolism and Epithelial Differentiation in Neonatal Patient-derived Airway Cells

Key Points

Abstract

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