Biomedicines (Aug 2021)

GRP78 Overexpression Triggers PINK1-IP<sub>3</sub>R-Mediated Neuroprotective Mitophagy

  • Tatiana Leiva-Rodríguez,
  • David Romeo-Guitart,
  • Mireia Herrando-Grabulosa,
  • Pau Muñoz-Guardiola,
  • Miriam Polo,
  • Celia Bañuls,
  • Valerie Petegnief,
  • Assumpció Bosch,
  • Jose Miguel Lizcano,
  • Nadezda Apostolova,
  • Joaquim Forés,
  • Caty Casas

DOI
https://doi.org/10.3390/biomedicines9081039
Journal volume & issue
Vol. 9, no. 8
p. 1039

Abstract

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An experimental model of spinal root avulsion (RA) is useful to study causal molecular programs that drive retrograde neurodegeneration after neuron-target disconnection. This neurodegenerative process shares common characteristics with neuronal disease-related processes such as the presence of endoplasmic reticulum (ER) stress and autophagy flux blockage. We previously found that the overexpression of GRP78 promoted motoneuronal neuroprotection after RA. After that, we aimed to unravel the underlying mechanism by carrying out a comparative unbiased proteomic analysis and pharmacological and genetic interventions. Unexpectedly, mitochondrial factors turned out to be most altered when GRP78 was overexpressed, and the abundance of engulfed mitochondria, a hallmark of mitophagy, was also observed by electronic microscopy in RA-injured motoneurons after GRP78 overexpression. In addition, GRP78 overexpression increased LC3-mitochondria tagging, promoted PINK1 translocation, mitophagy induction, and recovered mitochondrial function in ER-stressed cells. Lastly, we found that GRP78-promoted pro-survival mitophagy was mediated by PINK1 and IP3R in our in vitro model of motoneuronal death. This data indicates a novel relationship between the GRP78 chaperone and mitophagy, opening novel therapeutical options for drug design to achieve neuroprotection.

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