SIRT3 deficiency worsens eustachian tube dysfunction during middle-ear infection

Middle-ear infections caused by Gram-negative bacteria remain among the most common pediatric illnesses worldwide. When the eustachian tube-responsible for balancing pressure and clearing mucus-fails to function properly during infection, inflammation can persist and heighten the risk of chronic otitis media. Lipopolysaccharide (LPS), a major bacterial component, is widely used to model this inflammatory injury. Meanwhile, SIRT3, a mitochondrial regulator involved in energy homeostasis and inflammation control, has shown protective roles in the lung, kidney, heart, and nervous system. Yet its function in the middle ear has rarely been explored. Based on these challenges, there is a need to conduct in-depth research on the role of SIRT3 in infection-induced eustachian tube dysfunction.

Researchers from Tongji Medical College and collaborating hospitals report new findings (DOI: 10.26599/JOTO.2025.9540033) in the Journal of Otology (November 2025) showing that deficiency of SIRT3 significantly intensifies eustachian tube dysfunction following LPS-induced acute otitis media in mice. Through detailed imaging, mucus analysis, and pressure-regulation assessments, the team uncovered how the absence of SIRT3 heightens tissue vulnerability, leading to thicker mucus, weakened cilia, and impaired tube opening. The results offer mechanistic insight into how mitochondrial resilience influences the progression and severity of middle-ear infections.

To determine how SIRT3 shapes inflammatory responses in the ear, the researchers compared wild-type and SIRT3-knockout mice after injecting LPS into the middle ear. Under baseline conditions, both groups showed similar eustachian tube structure. However, once inflammation was triggered, their responses diverged sharply. Histological and immunohistochemical analyses revealed that SIRT3-deficient mice developed far more goblet-cell proliferation, abundant mucus plugs, and a striking elevation in MUC5AC expression-changes associated with denser, more adhesive mucus. Scanning electron microscopy further demonstrated pronounced shortening and loss of epithelial cilia, suggesting weakened mucociliary transport capacity.

Functional measurements echoed these structural findings. Following LPS treatment, SIRT3-knockout mice showed a markedly higher passive opening pressure, indicating increased resistance to tube opening. While neither SIRT3 deficiency nor LPS alone produced a substantial drop in mucociliary clearance, the combination caused a significant decline in transport distance. Their ability to actively clear negative pressure was also reduced under baseline conditions, implying that SIRT3 contributes to maintaining mechanical responsiveness.

Collectively, the results depict a clear narrative: without SIRT3, the eustachian tube becomes far more susceptible to inflammatory overload, as mucus thickens, cilia deteriorate, and pressure-regulation mechanisms fail.

"The eustachian tube may appear structurally simple, but its function relies on a delicate interplay of mucus properties, ciliary motion, and pressure-balancing mechanics," the research team noted. "Our findings show that SIRT3 acts as a stabilizing force during inflammation. When this mitochondrial regulator is absent, the system loses its resilience-mucus becomes heavier, clearance slows, and pressure equalization becomes more difficult. Understanding this protective role helps explain why certain individuals are more prone to chronic or recurrent ear infections and may guide new therapeutic strategies."

The discovery that SIRT3 governs mucus secretion, ciliary integrity, and pressure regulation suggests new therapeutic opportunities for treating eustachian tube dysfunction and preventing chronic otitis media. Enhancing SIRT3 activity-or targeting its downstream protective pathways-may help restore mucociliary function, reduce mucus obstruction, and accelerate recovery from infection-driven inflammation. Because excessive MUC5AC production and ciliary impairment also appear in respiratory diseases, these insights may extend beyond otology to broader airway research. Ultimately, therapies that strengthen mitochondrial resilience could reshape clinical approaches to persistent middle-ear and airway conditions.