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Receptor-interacting protein kinases modulate noise-induced sensory hair cell death

H-W Zheng1, J Chen1, S-H Sha1

  • 1Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.

Cell Death & Disease
|May 31, 2014
PubMed

Insights

Noise exposure triggers both apoptosis and necrosis in outer hair cells (OHCs). Inhibiting caspases shifts cell death to RIP kinase-dependent necrosis, while inhibiting RIP kinases promotes apoptosis, revealing dual modulation of OHC death pathways.

Area of Science:

  • Cell Biology
  • Auditory Neuroscience
  • Molecular Biology

Background:

  • Receptor-interacting protein (RIP) kinases are key regulators of necrotic cell death.
  • Outer hair cells (OHCs) are crucial for hearing and susceptible to noise-induced damage.
  • Understanding OHC death pathways is vital for developing hearing protection strategies.

Purpose of the Study:

  • To investigate RIP kinase-regulated necroptosis in outer hair cells (OHCs) following noise exposure.
  • To elucidate the interplay between apoptosis and necrosis in noise-induced OHC death.
  • To evaluate the therapeutic potential of inhibiting these cell death pathways.

Main Methods:

  • Adult male CBA/J mice were exposed to noise causing permanent threshold shifts.
  • Outer hair cells (OHCs) were analyzed for apoptotic and necrotic features.
  • Protein levels of RIP1, RIP3, and activated caspases were measured.
  • Pharmacological inhibitors (ZVAD, Necrostatin-1) and siRNA (siRIP3) were used to modulate cell death pathways.
  • Auditory brainstem response (ABR) tests assessed hearing function.

Main Results:

  • Noise exposure induced both apoptotic and necrotic features in OHC nuclei.
  • RIP1 and RIP3 protein levels increased, and caspase-8 was activated post-noise exposure.
  • ZVAD treatment blocked caspase-8, increased RIP kinases and necrosis, while Nec-1/siRIP3 reduced necrosis and increased apoptosis.
  • siRIP3 treatment promoted caspase-9 activation and endonuclease G translocation.
  • ZVAD treatment reduced noise-induced hearing deficits, an effect enhanced by combined siRIP3 treatment.

Conclusions:

  • Noise-induced outer hair cell (OHC) death is modulated by both caspases (apoptosis) and RIP kinases (necrosis).
  • Inhibiting one pathway redirects OHC death towards the alternative pathway.
  • Targeting these distinct cell death mechanisms offers potential therapeutic strategies for noise-induced hearing loss.

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