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Redox control of cell death
Shugo Ueda1, Hiroshi Masutani, Hajime Nakamura
1Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
Abstract:
Cellular redox is controlled by the thioredoxin (Trx) and glutathione (GSH) systems that scavenge harmful intracellular reactive oxygen species (ROS). Oxidative stress also evokes many intracellular events including apoptosis. There are two major pathways through which apoptosis is induced; one involves death receptors and is exemplified by Fas-mediated caspase-8 activation, and another is the stress- or mitochondria-mediated caspase-9 activation pathway. Both pathways converge on caspase-3 activation, resulting in nuclear degradation and cellular morphological change. Oxidative stress induces cytochrome c release from mitochondria and activation of caspases, p53, and kinases, including apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. Trx inhibits apoptosis signaling not only by scavenging intracellular ROS in cooperation with the GSH system, but also by inhibiting the activity of ASK1 and p38. Mitochondria-specific thioredoxin (Trx-2) and Trx peroxidases (peroxiredoxins) are suggested to regulate cytochrome c release from mitochondria, which is a critical early step in the apoptotis-signaling pathway. dATP/ATP and reducing factors including Trx determine the manifestation of cell death, apoptosis or necrosis, by regulating the activation process and the activity of redox-sensitive caspases. As mitochondria are the most redox-active organelle and indispensable for cells to initiate or inhibit the apoptosis process, the regulation of mitochondrial function is the central focus in the research field of apoptosis and redox.
Insights
The thioredoxin (Trx) and glutathione (GSH) systems manage cellular redox balance and combat reactive oxygen species (ROS). Trx also inhibits apoptosis signaling by scavenging ROS and blocking key kinases, highlighting its crucial role in cell death regulation.
Area of Science:
- Cellular Biology
- Biochemistry
- Oxidative Stress Research
Background:
- Cellular redox homeostasis is maintained by thioredoxin (Trx) and glutathione (GSH) systems, crucial for scavenging reactive oxygen species (ROS).
- Oxidative stress triggers intracellular events, including apoptosis, mediated by distinct pathways involving death receptors or mitochondria.
- Both apoptotic pathways converge on caspase-3 activation, leading to cellular degradation.
Purpose of the Study:
- To elucidate the role of Trx and GSH systems in regulating apoptosis under oxidative stress.
- To investigate the mechanisms by which Trx influences apoptosis signaling pathways, including kinase inhibition.
- To explore the mitochondrial regulation of apoptosis and its connection to cellular redox state.
Main Methods:
- Review of existing literature on cellular redox systems, oxidative stress, and apoptosis.
- Analysis of the molecular mechanisms involving Trx, GSH, caspases, p53, and kinases (ASK1, JNK, p38).
- Examination of the role of mitochondria-specific thioredoxin (Trx-2) and peroxiredoxins in cytochrome c release.
Main Results:
- Trx and GSH systems effectively scavenge ROS, mitigating oxidative stress.
- Trx actively inhibits apoptosis by scavenging ROS and suppressing the activity of ASK1 and p38 kinases.
- Mitochondria-specific Trx (Trx-2) and peroxiredoxins are implicated in regulating mitochondrial cytochrome c release, a key apoptotic event.
Conclusions:
- The thioredoxin system plays a dual role in apoptosis: ROS scavenging and direct inhibition of pro-apoptotic signaling kinases.
- Mitochondrial regulation of apoptosis is intrinsically linked to cellular redox state, with Trx and ATP/dATP influencing cell fate (apoptosis vs. necrosis).
- Mitochondria are central to apoptosis regulation, making their functional control a critical focus in redox and apoptosis research.