GLCCI1 ameliorates mitochondrial dysfunction in allergic asthma mice via DYRK1A/FAM117B-dependent NRF2 activation.

Abstract

Allergic asthma significantly impacts individuals' quality of life and work. This study aimed to investigate the specific mechanisms by which GLCCI1 regulated mitochondrial dysfunction in allergic asthma mice. In an ovalbumin (OVA)-induced allergic asthma mouse model, mitochondrial dysfunction in airway epithelium was observed, characterized by reduced ATP production, decreased mtDNA copy number, ROS accumulation, and mitophagy activation (upregulated PINK1/OPTN). In vitro experiments confirmed that OVA stimulation impaired mitochondrial membrane potential, exacerbated oxidative stress, and reduced cell viability in bronchial epithelial cells (BECs). Moreover, GLCCI1 regulated DYRK1A/FAM117B and KEAP1/NRF2 axis while inhibiting NRF2 ubiquitination degradation. Mechanistically, GLCCI1 overexpression reversed OVA-induced mitochondrial dysfunction by activating NRF2 signaling pathway via enhancing DYRK1A/FAM117B. In allergic asthma mice, GLCCI1 overexpression improved airway hyperresponsiveness, reduced inflammatory infiltration, restored alveolar structure, and decreased IL-4/IL-5/IL-13 levels. In summary, GLCCI1 ameliorated mitochondrial dysfunction in allergic asthma mice via the DYRK1A/FAM117B/NRF2 pathway, offering a potential therapeutic target for allergic asthma.