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Acta Pharmacologica Sinica Feb 2024Due to the sustained proliferative potential of cancer cells, inducing cell death is a potential strategy for cancer therapy. Paraptosis is a mode of cell death... (Review)
Review
Due to the sustained proliferative potential of cancer cells, inducing cell death is a potential strategy for cancer therapy. Paraptosis is a mode of cell death characterized by endoplasmic reticulum (ER) and/or mitochondrial swelling and cytoplasmic vacuolization, which is less investigated. Considerable evidence shows that paraptosis can be triggered by various chemical compounds, particularly in cancer cells, thus highlighting the potential application of this non-classical mode of cell death in cancer therapy. Despite these findings, there remain significant gaps in our understanding of the role of paraptosis in cancer. In this review, we summarize the current knowledge on chemical compound-induced paraptosis. The ER and mitochondria are the two major responding organelles in chemical compound-induced paraptosis, which can be triggered by the reduction of protein degradation, disruption of sulfhydryl homeostasis, overload of mitochondrial Ca, and increased generation of reactive oxygen species. We also discuss the stumbling blocks to the development of this field and the direction for further research. The rational use of paraptosis might help us develop a new paradigm for cancer therapy.
Topics: Paraptosis; Cell Line, Tumor; Cell Death; Reactive Oxygen Species; Endoplasmic Reticulum; Apoptosis; Neoplasms
PubMed: 37715003
DOI: 10.1038/s41401-023-01159-7 -
International Journal of Molecular... Sep 2023This review analyzes the causes and consequences of apoptosis resulting from oxidative stress that occurs in mitochondria and cells exposed to the toxic effects of... (Review)
Review
This review analyzes the causes and consequences of apoptosis resulting from oxidative stress that occurs in mitochondria and cells exposed to the toxic effects of different-valence heavy metals (Ag, Tl, Hg, Cd, Pb, Al, Ga, In, As, Sb, Cr, and U). The problems of the relationship between the integration of these toxic metals into molecular mechanisms with the subsequent development of pathophysiological processes and the appearance of diseases caused by the accumulation of these metals in the body are also addressed in this review. Such apoptosis is characterized by a reduction in cell viability, the activation of caspase-3 and caspase-9, the expression of pro-apoptotic genes ( and ), and the activation of protein kinases (ERK, JNK, p53, and p38) by mitogens. Moreover, the oxidative stress manifests as the mitochondrial permeability transition pore (MPTP) opening, mitochondrial swelling, an increase in the production of reactive oxygen species (ROS) and HO, lipid peroxidation, cytochrome c release, a decline in the inner mitochondrial membrane potential (ΔΨ), a decrease in ATP synthesis, and reduced glutathione and oxygen consumption as well as cytoplasm and matrix calcium overload due to Ca release from the endoplasmic reticulum (ER). The apoptosis and respiratory dysfunction induced by these metals are discussed regarding their interaction with cellular and mitochondrial thiol groups and Fe metabolism disturbance. Similarities and differences in the toxic effects of Tl from those of other heavy metals under review are discussed. Similarities may be due to the increase in the cytoplasmic calcium concentration induced by Tl and these metals. One difference discussed is the failure to decrease Tl toxicity through metallothionein-dependent mechanisms. Another difference could be the decrease in reduced glutathione in the matrix due to the reversible oxidation of Tl to Tl near the centers of ROS generation in the respiratory chain. The latter may explain why thallium toxicity to humans turned out to be higher than the toxicity of mercury, lead, cadmium, copper, and zinc.
Topics: Humans; Reactive Oxygen Species; Calcium; Hydrogen Peroxide; Mitochondrial Membrane Transport Proteins; Mitochondria; Apoptosis; Oxidative Stress; Cadmium; Glutathione; Metals, Heavy; Membrane Potential, Mitochondrial
PubMed: 37833908
DOI: 10.3390/ijms241914459 -
Oral Diseases Sep 2019Mitophagy is an important mitochondrial quality control mechanism. In this study, we investigated the mitochondrial damage and mitophagy occurred in inflammatory human...
OBJECTIVES
Mitophagy is an important mitochondrial quality control mechanism. In this study, we investigated the mitochondrial damage and mitophagy occurred in inflammatory human dental pulp and lipopolysaccharide-stimulated preodontoblasts.
MATERIALS AND METHODS
In dental pulp tissues and lipopolysaccharide-stimulated preodontoblasts, immunofluorescences and Western blot were performed to detect the expression of mitochondrial and mitophagy-related proteins, and autophagy markers were also examined. Reactive oxygen species generated by mitochondria were examined by MitoSOX. Transmission electron microscope (TEM) was used to examine the morphology of mitochondria in lipopolysaccharide-stimulated preodontoblasts.
RESULTS
The active fission activity of mitochondria and mitophagy in inflammatory dental pulp was observed. In lipopolysaccharide-treated preodontoblasts, mitophagy-related proteins were also upregulated. Moreover, increased reactive oxygen species in the inflamed preodontoblasts were observed. Additionally, single-membrane autolysosomes containing partially degraded mitochondria with swollen inner membranes in lipopolysaccharide-treated preodontoblasts were observed by TEM.
CONCLUSIONS
These results indicate that mitochondria were damaged and mitophagy might be activated to degrade impaired mitochondria in inflamed odontoblasts.
Topics: Humans; Mitochondria; Mitochondrial Swelling; Mitophagy; Odontoblasts; Protein Kinases; Ubiquitin-Protein Ligases
PubMed: 31009146
DOI: 10.1111/odi.13110 -
Basic Research in Cardiology Jun 2024Mitochondrial calcium (Ca) signals play a central role in cardiac homeostasis and disease. In the healthy heart, mitochondrial Ca levels modulate the rate of oxidative... (Review)
Review
Mitochondrial calcium (Ca) signals play a central role in cardiac homeostasis and disease. In the healthy heart, mitochondrial Ca levels modulate the rate of oxidative metabolism to match the rate of adenosine triphosphate consumption in the cytosol. During ischemia/reperfusion (I/R) injury, pathologically high levels of Ca in the mitochondrial matrix trigger the opening of the mitochondrial permeability transition pore, which releases solutes and small proteins from the matrix, causing mitochondrial swelling and ultimately leading to cell death. Pharmacological and genetic approaches to tune mitochondrial Ca handling by regulating the activity of the main Ca influx and efflux pathways, i.e., the mitochondrial Ca uniporter and sodium/Ca exchanger, represent promising therapeutic strategies to protect the heart from I/R injury.
PubMed: 38890208
DOI: 10.1007/s00395-024-01060-2 -
Nature Cell Biology Mar 2023Mitochondria are complex organelles with different compartments, each harbouring their own protein quality control factors. While chaperones of the mitochondrial matrix...
Mitochondria are complex organelles with different compartments, each harbouring their own protein quality control factors. While chaperones of the mitochondrial matrix are well characterized, it is poorly understood which chaperones protect the mitochondrial intermembrane space. Here we show that cytosolic small heat shock proteins are imported under basal conditions into the mitochondrial intermembrane space, where they operate as molecular chaperones. Protein misfolding in the mitochondrial intermembrane space leads to increased recruitment of small heat shock proteins. Depletion of small heat shock proteins leads to mitochondrial swelling and reduced respiration, while aggregation of aggregation-prone substrates is countered in their presence. Charcot-Marie-Tooth disease-causing mutations disturb the mitochondrial function of HSPB1, potentially linking previously observed mitochondrial dysfunction in Charcot-Marie-Tooth type 2F to its role in the mitochondrial intermembrane space. Our results reveal that small heat shock proteins form a chaperone system that operates in the mitochondrial intermembrane space.
Topics: Heat-Shock Proteins, Small; Molecular Chaperones; Mitochondria; Mitochondrial Proteins
PubMed: 36690850
DOI: 10.1038/s41556-022-01074-9 -
Canadian Journal of Physiology and... Sep 2019Age and sex play an essential role in the cardiac tolerance to ischemia-reperfusion injury: cardiac resistance significantly decreases during postnatal maturation and... (Review)
Review
Age and sex play an essential role in the cardiac tolerance to ischemia-reperfusion injury: cardiac resistance significantly decreases during postnatal maturation and the female heart is more tolerant than the male myocardium. It is widely accepted that mitochondrial dysfunction, and particularly mitochondrial permeability transition pore (MPTP) opening, plays a major role in determining the extent of cardiac ischemia-reperfusion injury. We have observed that the MPTP sensitivity to the calcium load differs in mitochondria isolated from neonatal and adult myocardium, as well as from adult male and female hearts. Neonatal and female mitochondria are more resistant both in the extent and in the rate of mitochondrial swelling induced by high calcium concentration. Our data further suggest that age- and sex-dependent specificity of the MPTP is not the result of different amounts of ATP synthase and cyclophilin D: neonatal and adult hearts, similarly as the male and female hearts, contain comparable amounts of MPTP and its regulatory protein cyclophilin D. We can speculate that the lower sensitivity of MPTP to the calcium-induced swelling may be related to the higher ischemic tolerance of both neonatal and female myocardium.
Topics: Animals; Calcium; Heart; Humans; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocardial Reperfusion Injury; Sex Characteristics
PubMed: 30893574
DOI: 10.1139/cjpp-2019-0060 -
Naunyn-Schmiedeberg's Archives of... Aug 2021The generation of a reactive nitrenium ion by microsomal/mitochondrial cytochrome P450 (CYPs) from clozapine (CLZ) has been suggested as the main cause of cardiotoxicity...
The generation of a reactive nitrenium ion by microsomal/mitochondrial cytochrome P450 (CYPs) from clozapine (CLZ) has been suggested as the main cause of cardiotoxicity by this drug. Previous studies indicated that thymoquinone (TQ) as an active constituent of Nigella sativa has pharmacological effects such as antioxidant, reactive oxygen species (ROS) scavenger, and inhibitory effect on CYPs enzymes. Therefore, we hypothesized that TQ with these pharmacological effects can reduce CLZ-induced toxicity in isolated cardiomyocytes and mitochondria. Rat left ventricular cardiomyocytes and mitochondria were isolated by collagenase perfusion and differential centrifugation respectively. Then, isolated cardiomyocytes and mitochondria were pretreated with different concentrations of TQ (1, 5, and 10 μmol/l) for 30 min and then followed by exposure to CLZ (50 μmol/l) for 6 h. After 6 h of incubation, using biochemical evaluations and flow cytometric analysis, the parameters of cellular toxicity including cytotoxicity, the level of oxidized/reduced glutathione (GSH/GSSG), malondialdehyde (MDA), reactive oxygen species (ROS) formation, lysosomal membrane integrity, mitochondria membrane potential (ΔΨm) collapse, and mitochondrial toxicity including succinate dehydrogenase (SDH) activity and mitochondrial swelling were analyzed. We observed a significant toxicity in isolated cardiomyocytes and mitochondria after exposure with CLZ which was related to ROS formation, oxidative stress, GSH depletion, lysosomal and mitochondrial damages, and mitochondrial dysfunction and swelling, while TQ pretreatment reverted the above toxic effect of CLZ on isolated cardiomyocytes and mitochondria. Our results indicate that TQ prevents and reverses CLZ-induced cytotoxicity and mitochondrial damages in isolated cardiomyocytes and mitochondria, providing an experimental basis for clinical treatment on CLZ-induced cardiotoxicity.
Topics: Animals; Antipsychotic Agents; Benzoquinones; Cardiotoxicity; Cell Death; Clozapine; Dose-Response Relationship, Drug; Glutathione; Male; Malondialdehyde; Membrane Potential, Mitochondrial; Mitochondria, Heart; Mitochondrial Swelling; Myocytes, Cardiac; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species
PubMed: 33937934
DOI: 10.1007/s00210-021-02095-1 -
Clinical Science (London, England :... Apr 2020Mitochondria are dynamic, undergoing both fission and fusion. Evidence indicates that a balance between these two processes is necessary to maintain a healthy state....
Mitochondria are dynamic, undergoing both fission and fusion. Evidence indicates that a balance between these two processes is necessary to maintain a healthy state. With ischemia/reperfusion (I/R) of the heart, fission is enhanced and is associated with mitochondrial swelling, depolarization, and production of reactive oxygen species (ROS), as well as apoptosis. Blocking fission is effective in reducing I/R-induced tissue damage and contractile dysfunction. In a groundbreaking study appearing in Clinical Science, Maneechote et al. assessed whether correcting the imbalance in mitochondrial dynamics with I/R by enhancing fusion would also be protective. Using a rat model, they investigated the efficacy of pharmacological intervention with mitochondrial fusion promoter-M1 (M1) given before ischemia, during ischemia, or at the onset of reperfusion. With pretreatment being the most effective, they found that M1 attenuated the incidence of arrhythmias, reduced infarct size, preserved cardiac function, and decreased mortality. M1 reduced I/R-induced increases in cytosolic cytochrome c, cleaved caspase 3, and apoptosis. All M1 groups exhibited modestly attenuated I/R-induced mitochondrial ROS levels and swelling, and preserved mitochondrial membrane potential. M1 also prevented a decrease in complex V levels with I/R. However, exactly how M1 stimulates mitochondrial fusion is unclear and other nonfusion-related actions of this phenylhydrazone compound should be considered, such as anti-oxidant actions, preconditioning signaling, or effects on putative mitochondrial connexin 43.
Topics: Animals; Apoptosis; Mitochondria; Mitochondrial Dynamics; Myocardial Infarction; Myocardial Reperfusion Injury; Rats; Reactive Oxygen Species; Ventricular Dysfunction, Left
PubMed: 32286622
DOI: 10.1042/CS20200236 -
Cell Death & Disease Jul 2019Noxa, a Bcl-2 homology 3 (BH3)-only protein of the Bcl-2 family, is responsive to cell stresses and triggers apoptosis by binding the prosurvival Bcl-2-like proteins...
Noxa, a Bcl-2 homology 3 (BH3)-only protein of the Bcl-2 family, is responsive to cell stresses and triggers apoptosis by binding the prosurvival Bcl-2-like proteins Mcl1, Bcl, and Bcl2A1. Although the Noxa BH3 domain is necessary to induce apoptosis, the mitochondrial targeting domain (MTD) of Noxa functions as a pronecrotic domain, an inducer of mitochondrial fragmentation, and delivery to mitochondria. In this study, we demonstrate that the extended MTD (eMTD) peptide induces necrotic cell death by interaction with the VDAC2 protein. The eMTD peptide penetrates the cell membrane, causing cell membrane blebbing, cytosolic calcium influx, and mitochondrial swelling, fragmentation, and ROS generation. The MTD domain binds VDACs and opens the mitochondrial permeability transition pore (mPTP) in a CypD-independent manner. The opening of mPTP induced by eMTD is inhibited either by down-regulation of VDAC2 or by the VDACs inhibitor DIDS. These results indicate that the MTD domain of Noxa causes mitochondrial damage by opening mPTP through VDACs, especially VDAC2, during necrotic cell death.
Topics: Amino Acid Sequence; Animals; Calcium; Cell Membrane; Cytosol; HEK293 Cells; HeLa Cells; Humans; Mice, Inbred BALB C; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Mitochondrial Swelling; Necrosis; Protein Binding; Protein Domains; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Structure-Activity Relationship; Voltage-Dependent Anion Channel 2
PubMed: 31285435
DOI: 10.1038/s41419-019-1753-4 -
Kidney360 Oct 2022Mitochondrial injury occurs in and underlies acute kidney injury (AKI) caused by ischemia-reperfusion and other forms of renal injury. However, to date, a comprehensive...
BACKGROUND
Mitochondrial injury occurs in and underlies acute kidney injury (AKI) caused by ischemia-reperfusion and other forms of renal injury. However, to date, a comprehensive analysis of this issue has not been undertaken in heme protein-induced AKI (HP-AKI). We examined key aspects of mitochondrial function, expression of proteins relevant to mitochondrial quality control, and mitochondrial ultrastructure in HP-AKI, along with responses to heme in renal proximal tubule epithelial cells.
METHODS
The long-established murine glycerol model of HP-AKI was examined at 8 and 24 hours after HP-AKI. Indices of mitochondrial function (ATP and NAD), expression of proteins relevant to mitochondrial dynamics, mitochondrial ultrastructure, and relevant gene/protein expression in heme-exposed renal proximal tubule epithelial cells were examined.
RESULTS
ATP and NAD content and the NAD/NADH ratio were all reduced in HP-AKI. Expression of relevant proteins indicate that mitochondrial biogenesis (PGC-1, NRF1, and TFAM) and fusion (MFN2) were impaired, as was expression of key proteins involved in the integrity of outer and inner mitochondrial membranes (VDAC, Tom20, and Tim23). Conversely, marked upregulation of proteins involved in mitochondrial fission (DRP1) occurred. Ultrastructural studies, including novel 3D imaging, indicate profound changes in mitochondrial structure, including mitochondrial fragmentation, mitochondrial swelling, and misshapen mitochondrial cristae; mitophagy was also observed. Exposure of renal proximal tubule epithelial cells to heme recapitulated suppression of PGC-1 (mitochondrial biogenesis) and upregulation of p-DRP1 (mitochondrial fission).
CONCLUSIONS
Modern concepts pertaining to AKI apply to HP-AKI. This study validates the investigation of novel, clinically relevant therapies such as NAD-boosting agents and mitoprotective agents in HP-AKI.
Topics: Mice; Animals; Hemeproteins; NAD; Acute Kidney Injury; Mitochondria; Heme; Adenosine Triphosphate
PubMed: 36514726
DOI: 10.34067/KID.0004832022