Inducers of chemical hypoxia act in a gender- and brain region-specific manner on primary astrocyte viability and cytochrome C oxidase.
Oxygen is the ultimate electron acceptor for mitochondrial respiration, a process catalyzed by cytochrome c oxidase (COX). In mammals, oxygen concentration regulates gene transcription of COX subunit IV isoforms. Here, we demonstrate that chemical hypoxia, i.e. inhibition of mitochondrial respiration by application of the COX inhibitors cobalt, cyanide, and azide, affects COX isoform IV-1 and IV-2 transcription in a gender- and brain region-specific way. After treatment with cyanide and cobalt, female cortical and mesencephalic astrocytes, respectively, revealed an up-regulation of COX IV-2 which was accompanied by increased ROS production and necrotic cell death. In male astrocytes, the ratio of COX IV-1/COX IV-2 was lowest after treatment with cobalt and paralleled by highest levels of ROS production and necrosis. These results support the view of a causal correlation of COX IV-2 transcription with cellular oxidative stress and cell death and highlight a gender specificity of these effects. By comparing three toxins, cobalt represented the most potent inducer of overall cell death and resembled most closely the previously observed effects of oxygen deprivation on decreasing the cox4i1/cox4i2 ratio. Overall, an increased sensitivity of male compared with female cell viability towards the toxins was detected. These regulatory responses might be causative for the known gender specificity of toxic and neurodegenerative processes in the brain.
Roemgens
André
A
Institute for Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany.
Singh
Shilpee
S
Beyer
Cordian
C
Arnold
Susanne
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D003035:Cobalt / Q000633:toxicity; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D003576:Electron Transport Complex IV / Q000096:biosynthesis; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D000860:Hypoxia / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007527:Isoenzymes / Q000096:biosynthesis; D008636:Mesencephalon / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis / Q000139:chemically induced; D011190:Potassium Cyanide / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D012727:Sex Characteristics; D019810:Sodium Azide / Q000633:toxicity; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D003035:Cobalt; D016861:Cyclooxygenase Inhibitors; D003576:Electron Transport Complex IV; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D011190:Potassium Cyanide; D017382:Reactive Oxygen Species; D019810:Sodium Azide; D000099162:Endothelial PAS Domain-Containing Protein 1; C018021:cobaltous chloride