title: Mitochondrial Optic Atrophy (OPA) 1 Processing Is Altered in Response to Neonatal Hypoxic-Ischemic Brain Injury.
abstract: Perturbation of mitochondrial function and subsequent induction of cell death pathways are key hallmarks in neonatal hypoxic-ischemic (HI) injury, both in animal models and in term infants. Mitoprotective therapies therefore offer a new avenue for intervention for the babies who suffer life-long disabilities as a result of birth asphyxia. Here we show that after oxygen-glucose deprivation in primary neurons or in a mouse model of HI, mitochondrial protein homeostasis is altered, manifesting as a change in mitochondrial morphology and functional impairment. Furthermore we find that the mitochondrial fusion and cristae regulatory protein, OPA1, is aberrantly cleaved to shorter forms. OPA1 cleavage is normally regulated by a balanced action of the proteases Yme1L and Oma1. However, in primary neurons or after HI in vivo, protein expression of YmelL is also reduced, whereas no change is observed in Oma1 expression. Our data strongly suggest that alterations in mitochondria-shaping proteins are an early event in the pathogenesis of neonatal HI injury.
authors.affiliation: Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, St. Thomas' Hospital, SE1 7EH London, UK. ana.baburamani@kcl.ac.uk.
authors.forename: Ana A
authors.initials: AA
authors.lastname: Baburamani
authors.affiliation: Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, St. Thomas' Hospital, SE1 7EH London, UK. chloe.hurling@kcl.ac.uk.
authors.forename: Chloe
authors.initials: C
authors.lastname: Hurling
authors.affiliation: Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, St. Thomas' Hospital, SE1 7EH London, UK. helen.stolp@kcl.ac.uk.
authors.forename: Helen
authors.initials: H
authors.lastname: Stolp
authors.affiliation: Perinatal Center, Institute for Clinical Sciences and Physiology & Neuroscience, Sahlgrenska Academy, University of Gothenburg, 41685 Gothenburg, Sweden. kristina.sobotka@gu.se.
authors.forename: Kristina
authors.initials: K
authors.lastname: Sobotka
authors.affiliation: Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, St. Thomas' Hospital, SE1 7EH London, UK. pierre.gressens@inserm.fr.|Inserm, U 1141, 75019 Paris, France. pierre.gressens@inserm.fr.|University Paris Diderot, Sorbonne Paris Cité, UMRS 1141, 75019 Paris, France. pierre.gressens@inserm.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.affiliation: Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, St. Thomas' Hospital, SE1 7EH London, UK. henrik.hagberg@kcl.ac.uk.|Perinatal Center, Institute for Clinical Sciences and Physiology & Neuroscience, Sahlgrenska Academy, University of Gothenburg, 41685 Gothenburg, Sweden. henrik.hagberg@kcl.ac.uk.
authors.forename: Henrik
authors.initials: H
authors.lastname: Hagberg
authors.affiliation: Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, St. Thomas' Hospital, SE1 7EH London, UK. claire.thornton@kcl.ac.uk.
authors.forename: Claire
authors.initials: C
authors.lastname: Thornton
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015687:Cell Hypoxia; D002460:Cell Line; D004195:Disease Models, Animal; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial; D008666:Metalloendopeptidases / Q000378:metabolism*; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000473:pathology / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D020558:GTP Phosphohydrolases; D008666:Metalloendopeptidases; D045726:Metalloproteases; D024101:Mitochondrial Proteins; C572960:OMA1 protein, mouse; C000588588:Yme1l1 protein, mouse; C498809:Opa1 protein, mouse
keywords: OPA1; Oma1; Yme1L; hypoxia-ischaemia; mitochondria; neonatal brain injury; oxygen-glucose deprivation (OGD)