title: Structural and functional damage sustained by mitochondria after traumatic brain injury in the rat: evidence for differentially sensitive populations in the cortex and hippocampus.
abstract: The cellular and molecular pathways initiated by traumatic brain injury (TBI) may compromise the function and structural integrity of mitochondria, thereby contributing to cerebral metabolic dysfunction and cell death. The extent to which TBI affects regional mitochondrial populations with respect to structure, function, and swelling was assessed 3 hours and 24 hours after lateral fluid-percussion brain injury in the rat. Significantly less mitochondrial protein was isolated from the injured compared with uninjured parietotemporal cortex, whereas comparable yields were obtained from the hippocampus. After injury, cortical and hippocampal tissue ATP concentrations declined significantly to 60% and 40% of control, respectively, in the absence of respiratory deficits in isolated mitochondria. Mitochondria with ultrastructural morphologic damage comprised a significantly greater percent of the population isolated from injured than uninjured brain. As determined by photon correlation spectroscopy, the mean mitochondrial radius decreased significantly in injured cortical populations (361 +/- 40 nm at 24 hours) and increased significantly in injured hippocampal populations (442 +/- 36 at 3 hours) compared with uninjured populations (Ctx: 418 +/- 44; Hipp: 393 +/- 24). Calcium-induced deenergized swelling rates of isolated mitochondrial populations were significantly slower in injured compared with uninjured samples, suggesting that injury alters the kinetics of mitochondrial permeability transition (MPT) pore activation. Cyclosporin A (CsA)-insensitive swelling was reduced in the cortex, and CsA-sensitive and CsA-insensitive swelling both were reduced in the hippocampus, demonstrating that regulated MPT pores remain in mitochondria isolated from injured brain. A proposed mitochondrial population model synthesizes these data and suggests that cortical mitochondria may be depleted after TBI, with a physically smaller, MPT-regulated population remaining. Hippocampal mitochondria may sustain damage associated with ballooned membranes and reduced MPT pore calcium sensitivity. The heterogeneous mitochondrial response to TBI may underlie posttraumatic metabolic dysfunction and contribute to the pathophysiology of TBI.
authors.affiliation: Head Injury Center, Department of Neurosurgery, University of Pensylvania, Philadelphia, Pensylvania 19104-6316, USA. jlifshit@mail.med.upenn.edu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lifshitz
authors.forename: Hans
authors.initials: H
authors.lastname: Friberg
authors.forename: Robert W
authors.initials: RW
authors.lastname: Neumar
authors.forename: Ramesh
authors.initials: R
authors.lastname: Raghupathi
authors.forename: Frank A
authors.initials: FA
authors.lastname: Welsh
authors.forename: Paul
authors.initials: P
authors.lastname: Janmey
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Saatman
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Wieloch
authors.forename: M Sean
authors.initials: MS
authors.lastname: Grady
authors.forename: Tracy K
authors.initials: TK
authors.lastname: McIntosh
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D001930:Brain Injuries / Q000473:pathology* / Q000503:physiopathology*; D002118:Calcium / Q000494:pharmacology; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology; D016572:Cyclosporine / Q000494:pharmacology; D004798:Enzymes / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology* / Q000502:physiology* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism; D010101:Oxygen Consumption; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004798:Enzymes; D024101:Mitochondrial Proteins; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D002118:Calcium