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

摘要

class="head no_bottom_margin" id="sec1title">IntroductionIn neurons, mitochondrial fission, which in mammals depends mainly on dynamin-related protein Drp1, facilitates both axonal mitochondrial transport and mitophagic elimination (, , , ). Not surprisingly, Drp1 is therefore required for brain development and mature neuronal function (, , , , , ). In several clinically and pathologically distinct neurodegenerative diseases, mitochondrial morphology is disrupted (reviewed by ), substantiating the link among mitochondrial dynamics, function, and brain pathophysiology. Given this, brain mitochondrial dysfunction could represent an important marker to identify subjects at risk of developing neurodegenerative disorders, before neurological symptoms manifest; however, no surrogate marker of brain mitochondrial dysfunction is available.Mitochondria of peripheral organs (e.g., liver and muscle) can convey disruption of their function by mounting cell-wide stress responses (, , , , href="#bib27" rid="bib27" class=" bibr popnode">Kim et al., 2013a, href="#bib45" rid="bib45" class=" bibr popnode">Touvier et al., 2015, href="#bib47" rid="bib47" class=" bibr popnode">Tyynismaa et al., 2010). A common trait of these models is the expression, causally linked to mitochondrial dysfunction, of the metabolic cytokine fibroblast growth factor 21 (Fgf21). This cytokine exerts a plethora of tissue-specific effects and is subject to complex pharmacology and pharmacokinetics, aspects of which continue to be matter of debate (reviewed by href="#bib25" rid="bib25" class=" bibr popnode">Kharitonenkov and DiMarchi, 2017). In addition to being canonically produced by liver and white adipose tissue (WAT) in response to starvation, Fgf21 can be secreted by other organs, such as pancreas and brown adipose tissue (href="#bib11" rid="bib11" class=" bibr popnode">Degirolamo et al., 2016, href="#bib15" rid="bib15" class=" bibr popnode">Fisher and Maratos-Flier, 2016). Moreover, Fgf21 has been established as a marker of mitochondrial myopathies (href="#bib43" rid="bib43" class=" bibr popnode">Suomalainen et al., 2011, href="#bib44" rid="bib44" class=" bibr popnode">Tezze et al., 2017). Whether Fgf21 is also produced by the CNS in response to mitochondrial dysfunction is unknown. Here we capitalize on our previously generated mouse model of inducible mitochondrial fission ablation in mature forebrain neurons (href="#bib35" rid="bib35" class=" bibr popnode">Oettinghaus et al., 2016), as well as on bona fide mouse models of neurodegeneration, to demonstrate that various forms of neuronal cell stress, including mitochondrial dysfunction, are sensed by the integrated stress response (ISR). In each of these models, ISR activation leads to neuron-specific Fgf21 expression, highlighting the potential of this cytokine as biomarker for neurodegenerative conditions.