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Mitochondrial ROS prime the hyperglycemic shift from apoptosis to necroptosis
Matthew A Deragon1, William D McCaig1, Payal S Patel1
1Department of Basic and Clinical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, 12208, USA.
Hyperglycemia shifts cell death from apoptosis to necroptosis, driven by reactive oxygen species (ROS) and RIP1. This shift worsens neonatal brain injury, highlighting a new therapeutic target.
Area of Science:
- Cellular biology
- Neuroscience
- Biochemistry
Background:
- Hyperglycemia induces a shift from TNF-α-induced apoptosis to necroptosis.
- This shift involves caspase downregulation and necrosome activation.
- This necroptosis exacerbates neonatal hypoxia-ischemia (HI) brain injury.
Purpose of the Study:
- Identify key factors driving the hyperglycemic shift to necroptosis.
- Investigate the role of reactive oxygen species (ROS) and RIP1 in this process.
- Determine the impact of this shift on neonatal HI brain injury.
Main Methods:
- Utilized in vivo models of neonatal hypoxia-ischemia (HI) in hyperglycemic mice.
- Assessed the role of reactive oxygen species (ROS), including mitochondrial superoxide.
- Investigated the function of receptor-interacting protein kinase 1 (RIP1) in cell death pathways.
Main Results:
- Identified ROS and RIP1 as major drivers of the hyperglycemic necroptosis shift.
- Demonstrated that ROS oxidize RIP1, activate the necrosome, and decrease executioner caspases.
- Showed that RIP1 partially regulates mitochondrial ROS levels and necroptosis activation.
- Confirmed that mitochondrial ROS exacerbate neonatal HI brain injury via necroptosis.
Conclusions:
- Hyperglycemia promotes necroptosis over apoptosis through ROS and RIP1.
- RIP1 and ROS interact to regulate cell death pathways and brain injury severity.
- Targeting ROS or RIP1 may mitigate hyperglycemic exacerbation of neonatal brain injury.
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