Mitochondrial permeability transition in CNS trauma: cause or effect of neuronal cell death?
Experimental traumatic brain injury (TBI) and spinal cord injury (SCI) result in a rapid and significant necrosis of neuronal tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the primary damage, resulting in significant neurologic dysfunction. It is believed that alterations in excitatory amino acids (EAA), increased reactive oxygen species (ROS), and the disruption of Ca(2+) homeostasis are major factors contributing to the ensuing neuropathology. Mitochondria serve as the powerhouse of the cell by maintaining ratios of ATP:ADP that thermodynamically favor the hydrolysis of ATP to ADP + P(i), yet a byproduct of this process is the generation of ROS. Proton-pumping by components of the electron transport system (ETS) generates a membrane potential (DeltaPsi) that can then be used to phosphorylate ADP or sequester Ca(2+) out of the cytosol into the mitochondrial matrix. This allows mitochondria to act as cellular Ca(2+) sinks and to be in phase with changes in cytosolic Ca(2+) levels. Under extreme loads of Ca(2+), however, opening of the mitochondrial permeability transition pore (mPTP) results in the extrusion of mitochondrial Ca(2+) and other high- and low-molecular weight components. This catastrophic event discharges DeltaPsi and uncouples the ETS from ATP production. Cyclosporin A (CsA), a potent immunosuppressive drug, inhibits mitochondrial permeability transition (mPT) by binding to matrix cyclophilin D and blocking its binding to the adenine nucleotide translocator. Peripherally administered CsA attenuates mitochondrial dysfunction and neuronal damage in an experimental rodent model of TBI, in a dose-dependent manner. The underlying mechanism of neuroprotection afforded by CsA is most likely via interaction with the mPTP because the immunosuppressant FK506, which has no effect on the mPT, was not neuroprotective. When CsA was administrated after experimental SCI at the same dosage and regimen used TBI paradigms, however, it had no beneficial neuroprotective effects. This review takes a comprehensive and critical look at the evidence supporting the role for mPT in central nervous system (CNS) trauma and highlights the differential responses of CNS mitochondria to mPT induction and the implications this has for therapeutically targeting the mPT in TBI and SCI.
Sullivan
P G
PG
Spinal Cord and Brain Injury Research Center, 240 HSRB, University of Kentucky, Lexington, KY 40536-0305, USA. PatSull@uky.edu
Rabchevsky
A G
AG
Waldmeier
P C
PC
Springer
J E
JE
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D016572:Cyclosporine / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000503:physiopathology; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010539:Permeability / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors
D004791:Enzyme Inhibitors; D016572:Cyclosporine; D002118:Calcium