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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., Graphical Abstract, Highlights • Neuronal Drp1 ablation is sensed by branches of the integrated stress response (ISR) • Activation of the ISR induces catabolic cytokine Fgf21 in the brain • Brain Fgf21 induced in neurodegeneration models may be a potential biomarker, 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.

During apoptosis mitochondria undergo cristae remodeling and fragmentation, but how the latter relates to outer membrane permeabilization and downstream caspase activation is unclear. Here we show that the mitochondrial fission protein Dynamin Related Protein (Drp) 1 participates in cytochrome c release by selected intrinsic death stimuli. While Bax, Bak double deficient (DKO) and Apaf1(-/-) mouse embryonic fibroblasts (MEFs) were less susceptible to apoptosis by Bcl-2 family member BID, H(2)O(2), staurosporine and thapsigargin, Drp1(-/-) MEFs were protected only from BID and H(2)O(2). Resistance to cell death of Drp1(-/-) and DKO MEFs correlated with blunted cytochrome c release, whereas mitochondrial fragmentation occurred in all cell lines in response to all tested stimuli, indicating that other mechanisms accounted for the reduced cytochrome c release. Indeed, cristae remodeling was reduced in Drp1(-/-) cells, potentially explaining their resistance to apoptosis. Our results indicate that caspase-independent mitochondrial fission and Drp1-dependent cristae remodeling amplify apoptosis. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.

Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphology in the hippocampus that are marginally responsive to antioxidant treatment. Furthermore, DRP1 loss affects synaptic transmission and memory function. Although these changes culminate in hippocampal atrophy, they are not sufficient to cause neuronal cell death within 10 weeks of genetic Drp1 ablation. Collectively, our in vivo observations clarify the role of mitochondrial fission in neurons, demonstrating that Drp1 ablation in adult forebrain neurons compromises critical neuronal functions without causing overt neurodegeneration.

14 páginas, 10 figuras. PMID:21984814[PubMed], The apoptotic protease activating factor 1 (Apaf1) is the main component of the apoptosome, and a crucial factor in the mitochondria-dependent death pathway. Here we show that Apaf1 plays a role in regulating centrosome maturation. By analyzing Apaf1-depleted cells, we have found that Apaf1 loss induces centrosome defects that impair centrosomal microtubule nucleation and cytoskeleton organization. This, in turn, affects several cellular processes such as mitotic spindle formation, cell migration and mitochondrial network regulation. As a consequence, Apaf1-depleted cells are more fragile and have a lower threshold to stress than wild-type cells. In fact, we found that they exhibit low Bcl-2 and Bcl-X(L) expression and, under apoptotic treatment, rapidly release cytochrome c. We also show that Apaf1 acts by regulating the recruitment of HCA66, with which it interacts, to the centrosome. This function of Apaf1 is carried out during the cell life and is not related to its apoptotic role. Therefore, Apaf1 might also be considered a pro-survival molecule, whose absence impairs cell performance and causes a higher responsiveness to stressful conditions, This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) [grant no. IG10081], the Telethon Foundation [grant no. S99038TELC], the Health and the Italian Ministry of University and Research [grant nos RF07.96M2, 020903305]. D. De Zio is a FILAS-Regione Lazio fellow.