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

Summary: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, MPTregulated 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.

Increased cerebral uptake and oxidation of exogenous βHB improves ATP following traumatic brain injury in adult rats

“…As a complement to this approach, we utilized an ATP bioluminescent imaging technique to generate regional information about the cerebral energy status. There was a 20% decrease in ipsilateral cortical ATP concentration 3 h after CCI injury alone, which is consistent with previous reports following TBI (Sullivan et al 1998;Lee et al 1999;Lifshitz et al 2003). Although the present studies did not address whether this decrease in ATP reflected cell death or dysfunction, there are several arguments that would suggest the latter.…”

Use of Magnesium in Traumatic Brain Injury

“…Generation of oxygen free radicals and mitochondrial dysfunctions lead to calcium accumulation, depletion of ATP, generation of reactive oxygen species, and apoptosis. 20,21 Together, these events result in neurodegeneration.…”

Excitotoxic Injury to Mitochondria Isolated from Cultured Neurons

“…Isolated mitochondria from different brain regions have been studied with regard to susceptibility to the permeability transition (41), susceptibility to dysfunction induced by traumatic brain injury (42), ischemic injury (27,43), and various toxicants (44) with the caveat that these are studies of mixed populations of mitochondria from varied cell types. The current approach allows more appropriate comparison of bioenergetic function between enriched neuronal cultures.…”