Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Tuberous sclerosis complex–mediated mTORC1 overactivation promotes age-related hearing loss
Xiaolong Fu, … , Haibo Wang, Jiangang Gao
Xiaolong Fu, … , Haibo Wang, Jiangang Gao
Published September 24, 2018
Citation Information: J Clin Invest. 2018;128(11):4938-4955. https://doi.org/10.1172/JCI98058.
View: Text | PDF
Research Article Aging Neuroscience

Tuberous sclerosis complex–mediated mTORC1 overactivation promotes age-related hearing loss

  • Text
  • PDF
Abstract

The underlying molecular mechanisms of age-related hearing loss (ARHL) in humans and many strains of mice have not been fully characterized. This common age-related disorder is assumed to be closely associated with oxidative stress. Here, we demonstrate that mTORC1 signaling is highly and specifically activated in the cochlear neurosensory epithelium (NSE) in aging mice, and rapamycin injection prevents ARHL. To further examine the specific role of mTORC1 signaling in ARHL, we generated murine models with NSE-specific deletions of Raptor or Tsc1, regulators of mTORC1 signaling. Raptor-cKO mice developed hearing loss considerably more slowly than WT littermates. Conversely, Tsc1 loss led to the early-onset death of cochlear hair cells and consequently accelerated hearing loss. Tsc1-cKO cochleae showed features of oxidative stress and impaired antioxidant defenses. Treatment with rapamycin and the antioxidant N-acetylcysteine rescued Tsc1-cKO hair cells from injury in vivo. In addition, we identified the peroxisome as the initial signaling organelle involved in the regulation of mTORC1 signaling in cochlear hair cells. In summary, our findings identify overactive mTORC1 signaling as one of the critical causes of ARHL and suggest that reduction of mTORC1 activity in cochlear hair cells may be a potential strategy to prevent ARHL.

Authors

Xiaolong Fu, Xiaoyang Sun, Linqing Zhang, Yecheng Jin, Renjie Chai, Lili Yang, Aizhen Zhang, Xiangguo Liu, Xiaochun Bai, Jianfeng Li, Haibo Wang, Jiangang Gao

×

Figure 10

Peroxisomes are involved in the regulation of mTORC1 in inner ear hair cells.

Options: View larger image (or click on image) Download as PowerPoint
Peroxisomes are involved in the regulation of mTORC1 in inner ear hair c...
(A–F) TEM analysis revealing the morphologies of mitochondria and peroxisomes in cochlear OHCs of WT and Tsc1-cKO mice at P28. (A and D) No mitochondrial abnormalities were seen at this time point in Tsc1-cKO mice compared with WT controls. The mitochondria showed normal morphologies with defined lamellar cristae. (B, C, E, F) Normally, peroxisomes (red arrowheads) demonstrate a circular cytoplasmic arrangement around a central nucleus in WT mice (B and E). However, many crystalline nuclei appeared in the peroxisomes of Tsc1-cKO OHCs (C), and several abnormal peroxisomes had no evident membrane structures (F). Scale bars: 1 μm (A–C), 0.5 μm (D–F). (G) Tsc1 is associated with peroxisomes in transfected HEI-OC1 cells. Transfected HEI-OC1 cells producing Tsc1 (Tsc1-GFP, green) were coimmunostained with an antibody against PMP70 (red). Cell nuclei were stained with DAPI (blue). Scale bar: 10 μm. (H) Corresponding line intensity measurements for each protein indicate strong colocalization of GFP (green) and PMP70 in peroxisomes. The fluorescence intensity was quantified using ImageJ (NIH). (I) Double immunolabeling of hair cells (IHCs and OHCs) for PMP70 (red) and endogenous Tsc1 (green). Scale bar: 10 μm. Three mice were examined for each genotype.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts