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

Restelli, Lisa Michelle; Oettinghaus, Björn; Halliday, Mark; Ağca, Cavit; Licci, Maria; Sironi, Lara; Savoia, Claudia; Hench, Jürgen; Tolnay, Markus; Neutzner, Albert; Schmidt, Alexander; Eckert, Anne; Mallucci, Giovanna R.; Scorrano, Luca; Frank, Stephan

doi:10.1016/j.celrep.2018.07.023

Cited by 77 publications

(72 citation statements)

References 53 publications

(85 reference statements)

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“…The presence of fibroblast growth factor 21 (FGF21) within the biomarker profile of PD is especially noticeable. Indeed, FGF21 has recently been related to dysfunctional MQC in neurons and has shown to be induced in brains of murine models of tauopathy and prion disease [155]. Thus, it is proposed that FGF21 may function as a "mitokine" and serve as a biomarker of mitochondrial dysfunction in the brain [155].…”

Section: Circulating Mitochondrial-derived Vesicles Systemic Inflammmentioning

confidence: 99%

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Picca

Calvani

Coelho-Júnior

et al. 2020

Cells

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Mitochondrial dysfunction and failing mitochondrial quality control (MQC) are major determinants of aging. Far from being standalone organelles, mitochondria are intricately related with cellular other compartments, including lysosomes. The intimate relationship between mitochondria and lysosomes is reflected by the fact that lysosomal degradation of dysfunctional mitochondria is the final step of mitophagy. Inter-organelle membrane contact sites also allow bidirectional communication between mitochondria and lysosomes as part of nondegradative pathways. This interaction establishes a functional unit that regulates metabolic signaling, mitochondrial dynamics, and, hence, MQC. Contacts of mitochondria with the endoplasmic reticulum (ER) have also been described. ER-mitochondrial interactions are relevant to Ca 2+ homeostasis, transfer of phospholipid precursors to mitochondria, and integration of apoptotic signaling. Many proteins involved in mitochondrial contact sites with other organelles also participate to degradative MQC pathways. Hence, a comprehensive assessment of mitochondrial dysfunction during aging requires a thorough evaluation of degradative and nondegradative inter-organelle pathways. Here, we present a geroscience overview on (1) degradative MQC pathways, (2) nondegradative processes involving inter-organelle tethering, (3) age-related changes in inter-organelle degradative and nondegradative pathways, and (4) relevance of MQC failure to inflammaging and age-related conditions, with a focus on Parkinson's disease as a prototypical geroscience condition.Cells 2020, 9, 598 2 of 18 instability, telomere attrition, epigenetic alterations, deregulated nutrient sensing, and stem cell exhaustion [3]. According to the geroscience hypothesis, perturbations in these mechanisms increase the susceptibility to most chronic diseases, functional loss, and eventually, death [4]. Hence, these biologic pillars represent ideal targets for interventions to foster healthy aging [5,6].Mitochondrial dysfunction has attracted considerable interest as a target for geroprotective interventions. Indeed, mitochondria play sensor-transducer-effector roles in a multitude of biological processes, including integration of cell death signaling and preservation of cell stemness [7,8]. Albeit long considered to be standalone organelles, a great deal of evidence indicates that mitochondria interact physically and functionally with other cellular compartments via membrane contact sites and tethering molecules [9,10]. In particular, mitochondria establish connections with the endosomal compartment [11,12] and lysosomes [13,14]. These interactions support cytosolic shuttle systems of ions and metabolites across organelles [10,15], and participate to the regulation of cellular housekeeping processes [13,14].The mitochondrial-lysosomal axis is a major actor in mitochondrial quality control (MQC), a hierarchical network of pathways that ensure organellar homeostasis through the coordination of mitochondrial proteostasis, dynamics, biogene...

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Section: Circulating Mitochondrial-derived Vesicles Systemic Inflammmentioning

confidence: 99%

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Picca

Calvani

Coelho-Júnior

et al. 2020

Cells

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“…Recent data indicate that to fully comprehend the phenotypic manifestations of mitochondrial diseases, it is crucial to take into account metabolic stress responses of the affected cells (Khan et al, 2017;Nikkanen et al, 2016;Restelli et al, 2018;Suomalainen & Battersby, 2018). A common feature observed in mouse models of mitochondrial diseases characterized by defects in mtDNA gene expression is the upregulation of the mitochondrial folate cycle and the serine biosynthesis pathway (Kuhl et al, 2017;Nikkanen et al, 2016).…”

Section: Deficiency Of the M-aaa Protease In Astrocytes Induces Infmentioning

confidence: 99%

Astrocyte‐specific deletion of the mitochondrial m‐AAA protease reveals glial contribution to neurodegeneration

Murru

Heß

Barth

et al. 2019

Glia

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Mitochondrial dysfunction causes neurodegeneration but whether impairment of mitochondrial homeostasis in astrocytes contributes to this pathological process remains largely unknown. The m ‐AAA protease exerts quality control and regulatory functions crucial for mitochondrial homeostasis. AFG3L2 , which encodes one of the subunits of the m ‐AAA protease, is mutated in spinocerebellar ataxia SCA28 and in infantile syndromes characterized by spastic‐ataxia, epilepsy and premature death. Here, we investigate the role of Afg3l2 and its redundant homologue Afg3l1 in the Bergmann glia (BG), radial astrocytes of the cerebellum that have functional connections with Purkinje cells (PC) and regulate glutamate homeostasis. We show that astrocyte‐specific deletion of Afg3l2 in the mouse leads to late‐onset motor impairment and to degeneration of BG, which display aberrant morphology, altered expression of the glutamate transporter EAAT2, and a reactive inflammatory signature. The neurological and glial phenotypes are drastically exacerbated when astrocytes lack both Afg31l and Afg3l2 , and therefore, are totally depleted of the m ‐AAA protease. Moreover, mitochondrial stress responses and necroptotic markers are induced in the cerebellum. In both mouse models, targeted BG show a fragmented mitochondrial network and loss of mitochondrial cristae, but no signs of respiratory dysfunction. Importantly, astrocyte‐specific deficiency of Afg3l1 and Afg3l2 triggers secondary morphological degeneration and electrophysiological changes in PCs, thus demonstrating a non‐cell‐autonomous role of glia in neurodegeneration. We propose that astrocyte dysfunction amplifies both neuroinflammation and glutamate excitotoxicity in patients carrying mutations in AFG3L2 , leading to a vicious circle that contributes to neuronal death.

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“…FGF21, which has been recognized as a prime lipid catabolic factor, plays an important role in regulating energy balance [20]. In recent years, it has been found that FGF21 could be an early biomarker for dysregulated mitochondrial dynamics and endoplasmic reticulum (ER) stress conditions and that it induces glial cells to promote remyelination in response to CNS disorders [40,41].…”

Section: Discussionmentioning

confidence: 99%

Microglia-derived FGF21 as a modulator of astrocytic phenotype and cerebral ischemia injury

Liu¹,

Wang²,

Zhu³

et al. 2020

Preprint

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Background: Fibroblast growth factor 21 (FGF21) is an important neuroprotective factor in the central nervous system (CNS), and it has been reported that FGF21 can protect against cerebral ischemia during the acute phase. However, the possible effects of FGF21 on ischemic brains and the interactions between FGF21 and nonneuronal cells have not been examined. Thus, the aim of this study was to elucidate the protective effects of endogenous FGF21 in ischemic brains.Methods: In this study, in vivo ischemia/reperfusion injury mouse model established by transient middle cerebral artery occlusion (MCAO)/reperfusion and in vitro cell models of oxygen/glucose deprivation (OGD)/reoxygenation (R) were used. Western blot analysis, RT-PCR, double immunofluorescence staining, immunohistochemistry, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (H&E) staining, neurobehavioral tests, cell counting kit-8 (CCK-8) assay and high-throughput gene sequencing were employed to explore the mechanism by which FGF21 unleash neuroprotective effort of astrocyte phenotype shifts in ischemic stroke.Results: We found that cortical FGF21 expression significantly increased after MCAO/reperfusion, peaking at 7 d. Ischemia-activated microglia were the main sources of endogenous FGF21 in brain tissue. However, FGF21 deficiency aggravated brain injury and slowed neurological functional recovery in FGF21 knockout mice. The in vitro and vivo studies revealed that FGF21 could activate astrocytes and mediate astrocytic phenotype. FGF21-activated astrocytes contributed to neuronal survival and synaptic protein upregulation after ischemia.Conclusion: Collectively, our data indicate that FGF21 plays vital roles in alleviating ischemic brain by mediating the manifestation of potentially pro-recovery astrocytic phenotypes. Therefore, modulation of FGF21 is a potential target strategy for stroke.

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

Cited by 77 publications

References 53 publications

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Astrocyte‐specific deletion of the mitochondrial m‐AAA protease reveals glial contribution to neurodegeneration

Microglia-derived FGF21 as a modulator of astrocytic phenotype and cerebral ischemia injury

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