Glutathione in Cerebral Microvascular Endothelial Biology and Pathobiology: Implications for Brain Homeostasis
Figure 2
Nuclear glutathione cycle and associated redox changes during cell cycle progression. A nuclear GSH cycle is established during cell cycle progression that involves the dynamic partitioning of cellular GSH between the nuclear and cytosolic compartments. Cell entry into the cycle in early G1 is associated with sequestration of GSH into the nucleus (A). At this stage of cell cycle initiation, the nuclear-to-cytosol (n/c) GSH ratio approximates 4. The transient decrease in cytosolic GSH releases feed-back inhibitory effect of GSH on GCL activity and triggers de novo GSH synthesis, a process that continues until the feedback control is reestablished. Sequestered intranuclear GSH exists in the reduced form or bound to nuclear proteins, which together changes the GSH/GSSG redox potential () in favor of gene transcription and cell cycle-associated DNA synthesis/replication. Free GSH functions in antioxidant defense that protects against oxidative DNA damage during DNA replication. As yet unclear, free GSH may be regenerated via deglutathiolation of thiolated nuclear proteins, likely catalyzed by Trx1 and/or Grx1. The dissolution of the nuclear envelope in the prometaphase and cytokinesis (cell cycle exit) induces nuclear-to-cytosol GSH export (B) resulting in equal GSH distribution (n/c = 1) in the two compartments in the newly divided cells. Redox-dependent activation of regulatory checkpoints governs cell exit from quiescence (cyclin D1 and associated Cdk4), entry into and progression through cell cycle (cyclin E1-Cdk2, cyclin A-Cdk2 kinase complexes), and final exit from cell cycle (cyclin B1-Cdk1 kinase complex) (blue arrows). Additionally the checkpoints at the G0/G1 or G1-to-S transitions can be bypassed by locally generated ROS (yellow arrows). GSH: glutathione, GSSG: glutathione disulfide, GCL: γ-glutamate cysteine ligase; n/c: nuclear-to-cytosol, Trx1: thioredoxin1, Grx1: glutaredoxin 1, and Cdk: cyclin-dependent kinase.
