Promoting TFEB nuclear localization with curcumin analog C1 attenuates sensory hair cell injury and delays age-related hearing loss in C57BL/6 mice

by Selleckchem | Nov 25 2023

Sensory hair cell (HC) injuries, especially outer hair cell (OHC) loss, are well-documented to be the primary pathology of age-related hearing loss (AHL). Recent studies have demonstrated that autophagy plays an important role in HC injury in the inner ear. In our previous works, a decline in autophagy levels and HC loss were found to occur simultaneously in the inner ears of aged C57BL/6 mice, and the administration of rapamycin promoted autophagy levels, which reduced OHC loss and delayed AHL, but the underlying mechanism of autophagy in AHL has not been well elucidated. Transcription factor EB (TFEB), an autophagy regulator and the downstream target of mammalian target of rapamycin (mTOR), is involved in the pathological development of neurodegenerative disease. This study would address the link between autophagy and TFEB in aged C57BL/6 mouse cochleae and clarify the effect of the TFEB activator curcumin analog C1 (C1) in aged cochleae. Decreased TFEB nuclear localization (p = 0.0371) and autophagy dysfunction (p = 0.0273) were observed in the cochleae of aged C57BL/6 mice that exhibited AHL, HCs loss and HCs senescence. Treatment with C1 promoted TFEB nuclear localization and restored autophagy, subsequently alleviating HC injury and delaying AHL. The protective effect of C1 on HEI-OC1 cells against autophagy disorder and aging induced by D-galactose was abolished by chloroquine, which is one of the commonly used autophagy inhibitors. Overall, our results demonstrated that the capacity to perform autophagy is mediated by the nuclear localization of TFEB in aged C57BL/6 mouse cochleae. C1 promotes the nuclear localization of TFEB, subsequently alleviating HC injury and delaying AHL by restoring the impaired autophagy function. TFEB may serve as a new therapeutic target for AHL treatment.

Comments:

The study you described explores the relationship between autophagy, specifically mediated by the transcription factor EB (TFEB), and age-related hearing loss (AHL) in aged C57BL/6 mouse cochleae. Here's a breakdown of the key findings and implications of the study:

### Background:
1. **AHL Pathology**: AHL is primarily caused by sensory hair cell (HC) injuries, especially outer hair cell (OHC) loss. Autophagy dysfunction has been linked to HC injury in the inner ear.

2. **Rapamycin Treatment**: Previous research demonstrated that rapamycin, an mTOR inhibitor, promoted autophagy, reduced OHC loss, and delayed AHL in aged mice.

### Current Study:
1. **Observations in Aged Mice Cochleae**:
- **Decreased TFEB Nuclear Localization**: Aged C57BL/6 mice with AHL showed reduced TFEB nuclear localization.
- **Autophagy Dysfunction**: Concurrently, these mice exhibited impaired autophagy function.

2. **Effect of C1 (Curcumin Analog)**:
    - **TFEB Nuclear Localization**: Treatment with C1, a curcumin analog, promoted TFEB nuclear localization.
    - **Restoration of Autophagy**: C1 treatment restored autophagy function in the cochleae.
    - **Alleviation of HC Injury and AHL Delay**: This restoration of impaired autophagy by C1 alleviated HC injury and delayed AHL progression.

3. **In Vitro Validation (HEI-OC1 cells)**:
- **Autophagy Disorder and Aging**: C1 protected HEI-OC1 cells against autophagy disorder and aging induced by D-galactose.
- **Inhibition by Chloroquine**: The protective effect of C1 was hindered by chloroquine, a common autophagy inhibitor.

### Implications:
1. **TFEB and Autophagy in AHL**: The study establishes that the ability to perform autophagy in the cochlea is regulated by TFEB's nuclear localization, highlighting the importance of this transcription factor in AHL.

2. **Therapeutic Potential of TFEB Activation**:
- **C1 as a Therapeutic Agent**: C1, by promoting TFEB nuclear localization and restoring autophagy, presents a potential therapeutic approach for AHL.
- **New Therapeutic Target**: TFEB emerges as a novel therapeutic target for AHL treatment, suggesting that therapies focused on enhancing TFEB activity could be explored.

3. **Inhibition by Chloroquine**: The inhibitory effect of chloroquine emphasizes the significance of autophagy in the mechanism of C1’s action, reinforcing the role of autophagy in AHL pathology.

In summary, this study provides valuable insights into the molecular mechanisms underlying AHL. By elucidating the relationship between TFEB, autophagy, and HC health, it opens avenues for developing targeted therapies aimed at preserving hearing function in aging individuals.