Neuronal Mitochondrial Dysfunction Activates the Integrated Stress Response to Induce Fibroblast Growth Factor 21

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