Department of Cell Biology, Physiology and Immunology, Institut de Neurociències (INc), Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, Spain
David Romeo-Guitart
Department of Cell Biology, Physiology and Immunology, Institut de Neurociències (INc), Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, Spain
Mireia Herrando-Grabulosa
Department of Cell Biology, Physiology and Immunology, Institut de Neurociències (INc), Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, Spain
Pau Muñoz-Guardiola
Department of Biochemistry and Molecular Biology, Institut de Neurociències (INc), Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, Spain
Miriam Polo
Service of Endocrinology University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46010 Valencia, Spain
Celia Bañuls
Service of Endocrinology University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46010 Valencia, Spain
Valerie Petegnief
Department of Brain Ischemia and Neurodegeneration, Institute for Biomedical Research of Barcelona (IIBB), Spanish Research Council (CSIC), Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), 08036 Barcelona, Spain
Assumpció Bosch
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 08193 Barcelona, Spain
Jose Miguel Lizcano
Department of Biochemistry and Molecular Biology, Institut de Neurociències (INc), Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, Spain
Nadezda Apostolova
CIBERehd, Department de Farmacologia, Facultat de Medicina, Universitat de Valencia, 46010 Valencia, Spain
Joaquim Forés
Hand and Peripheral Nerve Unit, Hospital Clínic i Provincial, Universitat de Barcelona, 08007 Barcelona, Spain
Caty Casas
Department of Cell Biology, Physiology and Immunology, Institut de Neurociències (INc), Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, Spain
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.
