title: Mitochondrial response in a toddler-aged swine model following diffuse non-impact traumatic brain injury.
abstract: Traumatic brain injury (TBI) is an important health problem, and a leading cause of death in children worldwide. Mitochondrial dysfunction is a critical component of the secondary TBI cascades. Mitochondrial response in the pediatric brain has limited investigation, despite evidence that the developing brain's response differs from that of the adult, especially in diffuse non-impact TBI. We performed a detailed evaluation of mitochondrial bioenergetics using high-resolution respirometry in a swine model of diffuse TBI (rapid non-impact rotational injury: RNR), and examined the cortex and hippocampus. A substrate-uncoupler-inhibitor-titration protocol examined the role of the individual complexes as well as the uncoupled maximal respiration. Respiration per mg of tissue was also related to citrate synthase activity (CS) as an attempt to control for variability in mitochondrial content following injury. Diffuse RNR stimulated increased complex II-driven respiration relative to mitochondrial content in the hippocampus compared to shams. LEAK (State 4o) respiration increased in both regions, with decreased respiratory ratios of convergent oxidative phosphorylation through complex I and II, compared to sham animals, indicating uncoupling of oxidative phosphorylation at 24h. The study suggests that proportionately, complex I contribution to convergent mitochondrial respiration was reduced in the hippocampus after RNR, with a simultaneous increase in complex-II driven respiration. Mitochondrial respiration 24h after diffuse TBI varies by location within the brain. We concluded that significant uncoupling of oxidative phosphorylation and alterations in convergent respiration through complex I- and complex II-driven respiration reveals therapeutic opportunities for the injured at-risk pediatric brain.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, 3401 Civic Center Blvd., Philadelphia, PA 19104, USA. Electronic address: kilbaugh@chop.edu.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Kilbaugh
authors.affiliation: Mitochondrial Medicine, Department of Clinical Sciences, Lund University, BMC A13, SE-221 84 Lund, Sweden. Electronic address: michael.karlsson@med.lu.se.
authors.forename: Michael
authors.initials: M
authors.lastname: Karlsson
authors.affiliation: Department of Bioengineering, University of Pennsylvania, 210 South 33rd Street, Philadelphia, PA 19104, USA. Electronic address: aduhaime@partners.org.
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Duhaime
authors.affiliation: Mitochondrial Medicine, Department of Clinical Sciences, Lund University, BMC A13, SE-221 84 Lund, Sweden. Electronic address: magnus.hansson@med.lu.se.
authors.forename: Magnus J
authors.initials: MJ
authors.lastname: Hansson
authors.affiliation: Mitochondrial Medicine, Department of Clinical Sciences, Lund University, BMC A13, SE-221 84 Lund, Sweden. Electronic address: eskil.elmer@med.lu.se.
authors.forename: Eskil
authors.initials: E
authors.lastname: Elmer
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, Boston, MA 02114, USA. Electronic address: margulie@seas.upenn.edu.
authors.forename: Susan S
authors.initials: SS
authors.lastname: Margulies
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D013552:Swine
keywords: In vivo studies; Large animal model of injury; Mitochondria; Pediatric brain injury; Traumatic brain injury