Neuronal Mitochondrial Dysfunction Activates the Integrated Stress Response to Induce Fibroblast Growth Factor 21
Lisa Michelle Restelli,
Björn Oettinghaus,
Mark Halliday,
Cavit Agca,
Maria Licci,
Lara Sironi,
Claudia Savoia,
Jürgen Hench,
Markus Tolnay,
Albert Neutzner,
Alexander Schmidt,
Anne Eckert,
Giovanna Mallucci,
Luca Scorrano,
Stephan Frank
Affiliations
Lisa Michelle Restelli
Division of Neuropathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel 4031, Switzerland; University of Basel, Basel 4001, Switzerland
Björn Oettinghaus
Division of Neuropathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel 4031, Switzerland
Mark Halliday
Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, UK
Cavit Agca
Departments of Biomedicine and Ophthalmology, University Hospital Basel, Basel 4031, Switzerland
Maria Licci
Department of Neurosurgery, University Hospital Basel, Basel 4031, Switzerland
Lara Sironi
Division of Neuropathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel 4031, Switzerland; University of Basel, Basel 4001, Switzerland
Claudia Savoia
Department of Biology, University of Padua, Padua 35121, Italy
Jürgen Hench
Division of Neuropathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel 4031, Switzerland
Markus Tolnay
Division of Neuropathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel 4031, Switzerland
Albert Neutzner
Departments of Biomedicine and Ophthalmology, University Hospital Basel, Basel 4031, Switzerland
Alexander Schmidt
Proteomics Core Facility, Biozentrum, University of Basel, Basel 4056, Switzerland
Anne Eckert
University Psychiatric Clinics, Basel 4025, Switzerland
Giovanna Mallucci
Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, UK; UK Dementia Research Institute at the University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0AH, UK
Luca Scorrano
Department of Biology, University of Padua, Padua 35121, Italy; Venetian Institute of Molecular Medicine, Padua 35129, Italy
Stephan Frank
Division of Neuropathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel 4031, Switzerland; Corresponding author
Summary: Stress adaptation is essential for neuronal health. While the fundamental role of mitochondria in neuronal development has been demonstrated, it is still not clear how adult neurons respond to alterations in mitochondrial function and how neurons sense, signal, and respond to dysfunction of mitochondria and their interacting organelles. Here, we show that neuron-specific, inducible in vivo ablation of the mitochondrial fission protein Drp1 causes ER stress, resulting in activation of the integrated stress response to culminate in neuronal expression of the cytokine Fgf21. Neuron-derived Fgf21 induction occurs also in murine models of tauopathy and prion disease, highlighting the potential of this cytokine as an early biomarker for latent neurodegenerative conditions. : Restelli et al. show that deletion of mitochondrial fission protein Drp1 in adult mouse neurons activates multiple stress-sensing pathways. These converge on the integrated stress response, resulting in neuron-specific expression of metabolic cytokine Fgf21. Cerebral induction of Fgf21 also occurs in mechanistically independent mouse models of protein misfolding-associated neurodegeneration. Keywords: Alzheimer’s disease, autophagy, biomarker, endoplasmic reticulum, heme, metabolism, mitochondria, neurodegeneration, tau, unfolded protein response
