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Updated: Apr 17, 2026
Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c
Published on: June 29, 2011
Role of mitochondria in apoptotic and necroptotic cell death in the developing brain
Claire Thornton1, Henrik Hagberg2
1Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London SE1 7EH, United Kingdom.
Insights
Hypoxic-ischemic encephalopathy causes delayed brain injury. Understanding its molecular mechanisms, including mitochondrial dysfunction and inflammation, is crucial for developing new neuroprotective therapies beyond therapeutic hypothermia.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Hypoxic-ischemic encephalopathy (HIE) causes secondary brain injury and delayed energy failure.
- Therapeutic hypothermia is the only current treatment for severe intrapartum asphyxia in infants, improving outcomes by preserving high-energy phosphates.
- Developing novel neuroprotective therapies requires a deep understanding of HIE's molecular cell death pathways.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying cell death in hypoxic-ischemic encephalopathy.
- To identify key pathways involved in secondary brain injury following HIE.
- To provide a foundation for the development of next-generation neuroprotective treatments.
Main Methods:
- Review of molecular events following hypoxia-ischemia, including oxidative stress, calcium dysregulation, and mitochondrial impairment.
- Analysis of apoptotic and necroptotic cell death pathways triggered by HIE.
- Examination of inflammatory signaling and death receptor activation in neurons and oligodendroglia.
Main Results:
- Hypoxia-ischemia leads to a toxic intracellular environment with reactive oxygen/nitrosative species and calcium overload.
- Mitochondrial respiration is suppressed, calcium signaling is dysregulated, and Bax-dependent mitochondrial permeabilization occurs.
- Inflammation activates death receptors, initiating caspase-dependent apoptosis and RIPK-dependent necroptosis, both converging on mitochondria.
Conclusions:
- HIE triggers complex cell death cascades involving mitochondrial dysfunction and inflammatory pathways.
- Understanding these molecular mechanisms is essential for designing targeted neuroprotective strategies.
- Further research into these pathways could lead to improved treatments for HIE and other brain injuries.
Abstract:
Hypoxic-ischemic encephalopathy induces secondary brain injury characterized by delayed energy failure. Currently, therapeutic hypothermia is the sole treatment available after severe intrapartum asphyxia in babies and acts to attenuate secondary loss of high energy phosphates improving both short- and long-term outcome. In order to develop the next generation of neuroprotective therapies, we urgently need to understand the underlying molecular mechanisms leading to cell death. Hypoxia-ischemia creates a toxic intracellular environment including accumulation of reactive oxygen/nitrosative species and intracellular calcium after the insult, inducing mitochondrial impairment. More specifically mitochondrial respiration is suppressed and calcium signaling is dysregulated. At a certain threshold, Bax-dependent mitochondrial permeabilization will occur leading to activation of caspase-dependent and apoptosis-inducing factor-dependent apoptotic cell death. In addition, hypoxia-ischemia induces inflammation, which leads to the release of TNF-α, TRAIL, TWEAK, FasL and Toll-like receptor agonists that will activate death receptors on neurons and oligodendroglia. Death receptors trigger apoptotic death via caspase-8 and necroptotic cell death through formation of the necrosome (composed of RIP1, RIP3 and MLKL), both of which converge at the mitochondria.
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