Role of sarcolemmal ATP-sensitive potassium channel in oxidative stress-induced apoptosis: mitochondrial connection

2008 ◽  
Vol 294 (3) ◽  
pp. H1317-H1325 ◽  
Author(s):  
Jasna Marinovic ◽  
Marko Ljubkovic ◽  
Anna Stadnicka ◽  
Zeljko J. Bosnjak ◽  
Martin Bienengraeber
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Specific Interaction ◽  
Protective Role ◽  
Apoptotic Cell Death ◽  
Apoptotic Pathway ◽  
Neonatal Cardiomyocytes ◽  
Channel Inhibition

From time of their discovery, sarcolemmal ATP-sensitive K+ (sarcKATP) channels were thought to have an important protective role in the heart during stress whereby channel opening protects the heart from stress-induced Ca2+ overload and resulting damage. In contrast, some recent studies indicate that sarcKATP channel closing can lead to cardiac protection. Also, the role of the sarcKATP channel in apoptotic cell death is unclear. In the present study, the effects of channel inhibition on apoptosis and the specific interaction between the sarcKATP channel and mitochondria were investigated. Apoptotic cell death of cultured HL-1 and neonatal cardiomyocytes following exposure to oxidative stress was significantly increased in the presence of sarcKATP channel inhibitor HMR-1098 as evidenced by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and caspase-3,7 assays. This was paralleled by an increased release of cytochrome c from mitochondria to cytosol, suggesting activation of the mitochondrial death pathway. sarcKATP channel inhibition during stress had no effect on Bcl-2, Bad, and phospho-Bad, indicating that the increase in apoptosis cannot be attributed to these modulators of the apoptotic pathway. However, monitoring of mitochondrial Ca2+ with rhod-2 fluorescent indicator revealed that mitochondrial Ca2+ accumulation during stress is potentiated in the presence of HMR-1098. In conclusion, this study provides novel evidence that opening of sarcKATP channels, through a specific Ca2+-related interaction with mitochondria, plays an important role in preventing cardiomyocyte apoptosis and mitochondrial damage during stress.

scholarly journals Proteases involved during oxidative stress-induced poly(ADP-ribose) polymerase-mediated cell death in Dictyostelium discoideum

Microbiology ◽  
2014 ◽  
Vol 160 (6) ◽  
pp. 1101-1111 ◽  
Author(s):  
Jyotika Rajawat ◽  
Tina Alex ◽  
Hina Mir ◽  
Ashlesha Kadam ◽  
Rasheedunnisa Begum
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Plasma Membrane ◽  
Dictyostelium Discoideum ◽  
Cathepsin D ◽  
Apoptotic Cell ◽  
Model System ◽  
Apoptotic Cell Death ◽  
Key Players

Apoptosis involves a cascade of caspase activation leading to the ordered dismantling of critical cell components. However, little is known about the dismantling process in non-apoptotic cell death where caspases are not involved. Dictyostelium discoideum is a good model system to study caspase-independent cell death where experimental accessibility of non-apoptotic cell death is easier and molecular redundancy is reduced compared with other animal models. Poly(ADP-ribose) polymerase (PARP) is one of the key players in cell death. We have previously reported the role of PARP in development and the oxidative stress-induced cell death of D. discoideum. D. discoideum possesses nine PARP genes and does not have a caspase gene, and thus it provides a better model system to dissect the role of PARP in caspase-independent cell death. The current study shows that non-apoptotic cell death in D. discoideum occurs in a programmed fashion where proteases cause mitochondrial membrane potential changes followed by plasma membrane rupture and early loss of plasma membrane integrity. Furthermore, the results suggest that calpains and cathepsin D, which are instrumental in dismantling the cell, act downstream of PARP. Thus, PARP, apoptosis inducing factor, calpains and cathepsin D are the key players in D. discoideum caspase-independent cell death, acting in a sequential manner.

scholarly journals Autophagy impairment as a key feature for acetaminophen-induced ototoxicity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tong Zhao ◽  
Tihua Zheng ◽  
Huining Yu ◽  
Bo Hua Hu ◽  
Bing Hu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Lysosomal Enzymes ◽  
Apoptotic Cell ◽  
Cell Damage ◽  
Treatment Strategies ◽  
Explant Culture ◽  
Apoptotic Cell Death ◽  
Lysosomal Dysfunction ◽  
Autophagic Degradation

AbstractMacroautophagy/autophagy is a highly conserved self-digestion pathway that plays an important role in cytoprotection under stress conditions. Autophagy is involved in hepatotoxicity induced by acetaminophen (APAP) in experimental animals and in humans. APAP also causes ototoxicity. However, the role of autophagy in APAP-induced auditory hair cell damage is unclear. In the present study, we investigated autophagy mechanisms during APAP-induced cell death in a mouse auditory cell line (HEI-OC1) and mouse cochlear explant culture. We found that the expression of LC3-II protein and autophagic structures was increased in APAP-treated HEI-OC1 cells; however, the degradation of SQSTM1/p62 protein, the yellow puncta of mRFP-GFP-LC3 fluorescence, and the activity of lysosomal enzymes decreased in APAP-treated HEI-OC1 cells. The degradation of p62 protein and the expression of lysosomal enzymes also decreased in APAP-treated mouse cochlear explants. These data indicate that APAP treatment compromises autophagic degradation and causes lysosomal dysfunction. We suggest that lysosomal dysfunction may be directly responsible for APAP-induced autophagy impairment. Treatment with antioxidant N-acetylcysteine (NAC) partially alleviated APAP-induced autophagy impairment and apoptotic cell death, suggesting the involvement of oxidative stress in APAP-induced autophagy impairment. Inhibition of autophagy by knocking down of Atg5 and Atg7 aggravated APAP-induced ER and oxidative stress and increased apoptotic cell death. This study provides a better understanding of the mechanism responsible for APAP ototoxicity, which is important for future exploration of treatment strategies for the prevention of hearing loss caused by ototoxic medications.

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