title: Mitochondria controlled by UCP2 determine hypoxia-induced synaptic remodeling in the cortex and hippocampus.
abstract: We have established that mitochondrial dynamics, under metabolic control, play crucial roles in the regulation of systemic metabolism by hypothalamic circuits. The role of mitochondrial dynamics in neurons in higher brain regions is, however, ill-defined. Here we show that early postnatal exposure of animals to temporal hypoxia followed by normoxia, a major metabolic challenge on brain cells, resulted in adaptive responses of neuronal mitochondria. The number and oxygen consumption of mitochondria in cortical and hippocampal neurons were altered, while mitochondria-endoplasmic reticulum (ER) interactions were preserved. These changes coincided with increased synaptic input of neurons in the cortex and hippocampus. We identified that the changing oxygen tension triggered mitochondrial uncoupling protein 2 (UCP2) expression and showed that UCP2 is crucial for these adaptive mitochondrial responses. In UCP2 KO mice, changing oxygen tension did not induce changes in mitochondrial parameters and function but decreased mitochondria-ER contacts and resulted in loss of synapses both in the cortex and hippocampus. These observations establish that mitochondrial location controlled by UCP2 is relevant for adaptive responses of neurons in cortical and hippocampal neurons and are relevant to perinatal hypoxia-triggered circuit adaptations.
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Varela
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Neuroscience at Yale Medical School, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Schwartz
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Neuroscience at Yale Medical School, USA. Electronic address: tamas.horvath@yale.edu.
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
mesh_terms: D000818:Animals; D002452:Cell Count; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D002534:Hypoxia, Brain / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D000071246:Uncoupling Protein 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2
keywords: Cortex; Hippocampus; Mitochondria; Perinatal hypoxia; Synaptic plasticity; UCP2