title: Acute focal brain damage alters mitochondrial dynamics and autophagy in axotomized neurons.
abstract: Mitochondria are key organelles for the maintenance of life and death of the cell, and their morphology is controlled by continual and balanced fission and fusion dynamics. A balance between these events is mandatory for normal mitochondrial and neuronal function, and emerging evidence indicates that mitochondria undergo extensive fission at an early stage during programmed cell death in several neurodegenerative diseases. A pathway for selective degradation of damaged mitochondria by autophagy, known as mitophagy, has been described, and is of particular importance to sustain neuronal viability. In the present work, we analyzed the effect of autophagy stimulation on mitochondrial function and dynamics in a model of remote degeneration after focal cerebellar lesion. We provided evidence that lesion of a cerebellar hemisphere causes mitochondria depolarization in axotomized precerebellar neurons associated with PTEN-induced putative kinase 1 accumulation and Parkin translocation to mitochondria, block of mitochondrial fusion by Mfn1 degradation, increase of calcineurin activity and dynamin-related protein 1 translocation to mitochondria, and consequent mitochondrial fission. Here we suggest that the observed neuroprotective effect of rapamycin is the result of a dual role: (1) stimulation of autophagy leading to damaged mitochondria removal and (2) enhancement of mitochondria fission to allow their elimination by mitophagy. The involvement of mitochondrial dynamics and mitophagy in brain injury, especially in the context of remote degeneration after acute focal brain damage, has not yet been investigated, and these findings may offer new target for therapeutic intervention to improve functional outcomes following acute brain damage.
authors.affiliation: Department of Experimental Neurosciences, IRCCS S. Lucia Foundation, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Cavallucci
authors.affiliation: Department of Experimental Neurosciences, IRCCS S. Lucia Foundation, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Bisicchia
authors.affiliation: Department of Experimental Neurosciences, IRCCS S. Lucia Foundation, Rome, Italy.
authors.forename: M T
authors.initials: MT
authors.lastname: Cencioni
authors.affiliation: Institute of Cellular Biology and Neurobiology CNR, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Ferri
authors.affiliation: Department of Experimental Neurosciences, IRCCS S. Lucia Foundation, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Latini
authors.affiliation: 1] Department of Experimental Neurosciences, IRCCS S. Lucia Foundation, Rome, Italy [2] University Campus Bio-Medico, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Nobili
authors.affiliation: Institute of Histology and Embryology, Catholic University of Sacred Heart, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Biamonte
authors.affiliation: Department of Experimental Neurosciences, IRCCS S. Lucia Foundation, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Nazio
authors.affiliation: University Campus Bio-Medico, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Fanelli
authors.affiliation: Department of Biology-LIME, University 'Roma Tre', Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Moreno
authors.affiliation: Department of Experimental Neurosciences, IRCCS S. Lucia Foundation, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Molinari
authors.affiliation: Department of Experimental Neurosciences, IRCCS S. Lucia Foundation, Rome, Italy.
authors.forename: M T
authors.initials: MT
authors.lastname: Viscomi
authors.affiliation: 1] Department of Experimental Neurosciences, IRCCS S. Lucia Foundation, Rome, Italy [2] University Campus Bio-Medico, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: D'Amelio
mesh_terms: D000208:Acute Disease; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D019771:Axotomy; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology*; D019703:Calcineurin / Q000378:metabolism; D002531:Cerebellum / Q000601:surgery; D034281:Dynamins / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects; D063306:Mitophagy / Q000187:drug effects; D008954:Models, Biological; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D019703:Calcineurin; C486391:Dnm1l protein, mouse; D034281:Dynamins; D020123:Sirolimus