Role of Calcium Homeostasis in Ischemic Stroke: A Review

2021 ◽  
Vol 20 ◽  
Author(s):  
Abhilash Ludhiadch ◽  
Rashmi Sharma ◽  
Aishwarya Muriki ◽  
Anjana Munshi
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Neuronal Death ◽  
Complex Disease ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Vital Role ◽  
Calcium Accumulation ◽  
Cell Death Pathway

: Stroke is the second most common cause of death worldwide. It occurs due to the insufficient supply of oxygen-rich blood to the brain. It is a complex disease with multiple associated risk factors including smoking, alcoholism, age, sex, ethnicity, etc. Calcium ions are known to play a vital role in cell death pathways, which is a ubiquitous intracellular messenger during and immediately after an ischemic period. Disruption in normal calcium hemostasis is known to be a major initiator and activator of the ischemic cell death pathway. Under Ischemic stroke conditions, glutamate is released from the neurons and glia which further activates the N-methyl-D-aspartate (NMDA) receptor and triggers the rapid translocation of Ca2+ from extracellular to intracellular spaces in cerebral tissues and vice versa. Various studies indicated that Ca2+ could have harmful effects on neurons under acute ischemic conditions. Mitochondrial dysfunction also contributes to delayed neuronal death, and it was established decades ago that massive calcium accumulation triggers mitochondrial damage. Elevated Ca2+ levels cause mitochondria to swell and release their contents. As a result oxidative stress and mitochondrial calcium accumulation activate mitochondrial permeability transition and lead to depolarization-coupled production of reactive oxygen species. This association between calcium levels and mitochondrial death suggests that elevated calcium levels might have a role in the neurological outcome in ischemic stroke. Previous studies have also reported that elevated Ca2+ levels play a role in the determination of infarct size, outcome, and recurrence of ischemic stroke. The current review has been compiled to understand the multidimensional role of altered Ca2+ levels in the initiation and alteration of neuronal death after ischemic attack. The underlying mechanisms understood to date have also been discussed.

scholarly journals JNK1/2 regulates ER–mitochondrial Ca2+ cross-talk during IL-1β–mediated cell death in RINm5F and human primary β-cells

2013 ◽  
Vol 24 (12) ◽  
pp. 2058-2071 ◽  
Author(s):  
Gaurav Verma ◽  
Himanshi Bhatia ◽  
Malabika Datta
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Mitochondrial Permeability Transition ◽  
Apoptotic Cell ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Β Cells ◽  
Mediating Role ◽  
Induced Apoptosis

Elevated interleukin-1β (IL-1β) induces apoptosis in pancreatic β-cells through endoplasmic reticulum (ER) stress induction and subsequent c-jun-N-terminal kinase 1/2 (JNK1/2) activation. In earlier work we showed that JNK1/2 activation is initiated before ER stress and apoptotic induction in response to IL-1β. However, the detailed regulatory mechanisms are not completely understood. Because the ER is the organelle responsible for Ca2+ handling and storage, here we examine the effects of IL-1β on cellular Ca2+ movement and mitochondrial dysfunction and evaluate the role of JNK1/2. Our results show that in RINm5F cells and human primary β-cells, IL-1β alters mitochondrial membrane potential, mitochondrial permeability transition pore opening, ATP content, and reactive oxygen species production and these alterations are preceded by ER Ca2+ release via IP3R channels and mitochondrial Ca2+ uptake. All these events are prevented by JNK1/2 small interfering RNA (siRNA), indicating the mediating role of JNK1/2 in IL-1β–induced cellular alteration. This is accompanied by IL-1β–induced apoptosis, which is prevented by JNK1/2 siRNA and the IP3R inhibitor xestospongin C. This suggests a regulatory role of JNK1/2 in modulating the ER-mitochondrial-Ca2+ axis by IL-1β in apoptotic cell death.

scholarly journals Different Roles of Mitochondria in Cell Death and Inflammation: Focusing on Mitochondrial Quality Control in Ischemic Stroke and Reperfusion

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 169
Author(s):  
Marianna Carinci ◽  
Bianca Vezzani ◽  
Simone Patergnani ◽  
Peter Ludewig ◽  
Katrin Lessmann ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Molecular Mechanisms ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Brain Diseases ◽  
Cell Death Pathways ◽  
Molecular Pattern ◽  
Neuroprotective Strategies

Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. An insufficient supply of oxygen and glucose in brain cells, primarily neurons, triggers a cascade of events in which mitochondria are the leading characters. Mitochondrial calcium overload, reactive oxygen species (ROS) overproduction, mitochondrial permeability transition pore (mPTP) opening, and damage-associated molecular pattern (DAMP) release place mitochondria in the center of an intricate series of chance interactions. Depending on the degree to which mitochondria are affected, they promote different pathways, ranging from inflammatory response pathways to cell death pathways. In this review, we will explore the principal mitochondrial molecular mechanisms compromised during ischemic and reperfusion injury, and we will delineate potential neuroprotective strategies targeting mitochondrial dysfunction and mitochondrial homeostasis.

Abstract 173: The Role of Bax and Bak in Autophagic Cell Death

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Jason Karch ◽  
Tobias G Schips ◽  
Matthew J Brody ◽  
Onur Kanisicak ◽  
Michelle A Sargent ◽  
...  
Keyword(s):  
Cell Death ◽  
Membrane Permeability ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Autophagic Cell Death ◽  
Serum Starvation ◽  
Cytochrome C Release ◽  
Energy Depletion ◽  
Regulated Necrosis

In times of energy depletion, a cell will attempt to maintain metabolic homeostasis and viability by degrading and recycling organelles and intracellular components and proteins in a process referred to as autophagy. However, if the energy depletion persists, the cell will be overwhelmed by the autophagic process and will succumb to autophagic cell death. This form of cell death has been implicated in cardiac remodeling during heart failure and damage during ischemic injury. Two proteins that have been previously shown to play a role in virtually every form of regulated cell death, including autophagy, are Bax and Bak. These effectors are responsible for cytochrome-c release during apoptosis and effect mitochondrial permeability transition pore opening during regulated necrosis. Although the expression of either Bax or Bak is required for autophagic cell death to occur, the role of Bax/Bak in this type of cell death is poorly understood, although the lysosome appears to be centrally involved. Here we show that Bax/Bak DKO MEFs subjected to several days of serum starvation contain intact lysosomes compared to WT MEFs. Furthermore, the acidity of the lysosomes in starved DKO MEFs is preserved compared with starved WT MEFs. Bax and Bak are both found in isolated lysosomal preparations and Bax targeted to the lysosome can completely restore autophagic cell death in DKO MEFs. Finally, although Bax oligomerization is required for apoptosis, it is not necessary for autophagic cell death, as DKO MEFs expressing an oligomerization defective mutant of Bax are still susceptible to this form of death, as monomeric Bax can still increase membrane permeability. In conclusion our results suggest that lysosomal membrane permeability through Bax or Bak is required for autophagic cell death to occur and without Bax or Bak the lysosomes remain intact where they can function as an energy source during times of nutrient deprivation.

scholarly journals Adenine Nucleotide (ADP/ATP) Translocase 3 Participates in the Tumor Necrosis Factor–induced Apoptosis of MCF-7 Cells

2007 ◽  
Vol 18 (11) ◽  
pp. 4681-4689 ◽  
Author(s):  
Ziqiang Yang ◽  
Wei Cheng ◽  
Lixin Hong ◽  
Wanze Chen ◽  
Yanhai Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Tnf Α ◽  
Induced Apoptosis ◽  
Necrosis Factor ◽  
Mcf 7

Mitochondrial adenine nucleotide translocase (ANT) is believed to be a component or a regulatory component of the mitochondrial permeability transition pore (mtPTP), which controls mitochondrial permeability transition during apoptosis. However, the role of ANT in apoptosis is still uncertain, because hepatocytes isolated from ANT knockout and wild-type mice are equally sensitive to TNF- and Fas-induced apoptosis. In a screen for genes required for tumor necrosis factor α (TNF-α)-induced apoptosis in MCF-7 human breast cancer cells using retrovirus insertion–mediated random mutagenesis, we discovered that the ANT3 gene is involved in TNF-α–induced cell death in MCF-7 cells. We further found that ANT3 is selectively required for TNF- and oxidative stress–induced cell death in MCF-7 cells, but it is dispensable for cell death induced by several other inducers. This data supplements previous data obtained from ANT knockout studies, indicating that ANT is involved in some apoptotic processes. We found that the resistance to TNF-α–induced apoptosis observed in ANT3 mutant (ANT3mut) cells is associated with a deficiency in the regulation of the mitochondrial membrane potential and cytochrome c release. It is not related to intracellular ATP levels or survival pathways, supporting a previous model in which ANT regulates mtPTP. Our study provides genetic evidence supporting a role of ANT in apoptosis and suggests that the involvement of ANT in cell death is cell type– and stimulus-dependent.

Sign in / Sign up

Export Citation Format

Share Document