title: The mitochondrial permeability transition pore regulates nitric oxide-mediated apoptosis of neurons induced by target deprivation.
abstract: Ablation of mouse occipital cortex induces precisely timed and uniform p53-modulated and Bax-dependent apoptosis of thalamocortical projection neurons in the dorsal lateral geniculate nucleus (LGN) by 7 d after lesion. We tested the hypothesis that this neuronal apoptosis is initiated by oxidative stress and the mitochondrial permeability transition pore (mPTP). Preapoptotic LGN neurons accumulate mitochondria, Zn(2+) and Ca(2+), and generate higher levels of reactive oxygen species (ROS), including superoxide, nitric oxide (NO), and peroxynitrite, than LGN neurons with an intact cortical target. Preapoptosis of LGN neurons is associated with increased formation of protein carbonyls, protein nitration, and protein S-nitrosylation. Genetic deletion of nitric oxide synthase 1 (nos1) and inhibition of NOS1 with nitroindazole protected LGN neurons from apoptosis, revealing NO as a mediator. Putative components of the mPTP are expressed in mouse LGN, including the voltage-dependent anion channel (VDAC), adenine nucleotide translocator (ANT), and cyclophilin D (CyPD). Nitration of CyPD and ANT in LGN mitochondria occurs by 2 d after cortical injury. Chemical cross-linking showed that LGN neuron preapoptosis is associated with formation of CyPD and VDAC oligomers, consistent with mPTP formation. Mice without CyPD are rescued from neuron apoptosis as are mice treated with the mPTP inhibitors TRO-19622 (cholest-4-en-3-one oxime) and TAT-Bcl-X(L)-BH4. Manipulation of the mPTP markedly attenuated the early preapoptotic production of reactive oxygen/nitrogen species in target-deprived neurons. Our results demonstrate in adult mouse brain neurons that the mPTP functions to enhance ROS production and the mPTP and NO trigger apoptosis; thus, the mPTP is a target for neuroprotection in vivo.
authors.affiliation: Department of Pathology, Division of Neuropathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. martinl@jhmi.edu
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Neal A
authors.initials: NA
authors.lastname: Adams
authors.forename: Yan
authors.initials: Y
authors.lastname: Pan
authors.forename: Ann
authors.initials: A
authors.lastname: Price
authors.forename: Margaret
authors.initials: M
authors.lastname: Wong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002783:Cholestenones / Q000494:pharmacology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D003655:Decerebrate State / Q000503:physiopathology*; D007839:Functional Laterality / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005829:Geniculate Bodies / Q000378:metabolism / Q000473:pathology; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency; D009593:Nitroimidazoles / Q000494:pharmacology; D009778:Occipital Lobe / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism; D015032:Zinc / Q000378:metabolism; D051020:bcl-X Protein / Q000494:pharmacology
chemical_list: D002783:Cholestenones; D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009593:Nitroimidazoles; C000631446:PPIF protein, mouse; D017382:Reactive Oxygen Species; D050994:Voltage-Dependent Anion Channels; D051020:bcl-X Protein; D009569:Nitric Oxide; D000226:Mitochondrial ADP, ATP Translocases; C522838:olesoxime; D052248:Nitric Oxide Synthase Type I; D021983:Cyclophilins; D015032:Zinc; D002118:Calcium