scholarly journals Acetaminophen Hepatotoxicity

2019 ◽  
Vol 39 (02) ◽  
pp. 221-234 ◽  
Author(s):  
Anup Ramachandran ◽  
Hartmut Jaeschke
Keyword(s):  
Inflammatory Response ◽  
Oxidant Stress ◽  
Mitochondrial Protein ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Inflammatory Cells ◽  
The United States ◽  
Therapeutic Interventions ◽  
Glutathione Depletion ◽  
Apap Overdose

AbstractAcetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity. This insight led to the rapid introduction of N-acetylcysteine as a clinical antidote. However, more recently, substantial progress was made in further elucidating the detailed mechanisms of APAP-induced cell death. Mitochondrial protein adducts trigger a mitochondrial oxidant stress, which requires amplification through a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK) in the cytosol and translocation of phospho-JNK to the mitochondria. The enhanced oxidant stress is responsible for the membrane permeability transition pore opening and the membrane potential breakdown. The ensuing matrix swelling causes the release of intermembrane proteins such as endonuclease G, which translocate to the nucleus and induce DNA fragmentation. These pathophysiological signaling mechanisms can be additionally modulated by removing damaged mitochondria by autophagy and replacing them by mitochondrial biogenesis. Importantly, most of the mechanisms have been confirmed in human hepatocytes and indirectly through biomarkers in plasma of APAP overdose patients. The extensive necrosis caused by APAP overdose leads to a sterile inflammatory response. Although recruitment of inflammatory cells is necessary for removal of cell debris in preparation for regeneration, these cells have the potential to aggravate the injury. This review touches on the newest insight into the intracellular mechanisms of APAP-induced cells death and the resulting inflammatory response. Furthermore, it discusses the translation of these findings to humans and the emergence of new therapeutic interventions.

scholarly journals Mitochondrial Calcium Deregulation in the Mechanism of Beta-Amyloid and Tau Pathology

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2135 ◽  
Author(s):  
Noemi Esteras ◽  
Andrey Y. Abramov
Keyword(s):  
Neuronal Death ◽  
Neuronal Loss ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Therapeutic Interventions ◽  
Tau Pathology ◽  
Excitable Cells ◽  
Calcium Deregulation ◽  
Underlying Causes ◽  
Β Amyloid

Aggregation and deposition of β-amyloid and/or tau protein are the key neuropathological features in neurodegenerative disorders such as Alzheimer’s disease (AD) and other tauopathies including frontotemporal dementia (FTD). The interaction between oxidative stress, mitochondrial dysfunction and the impairment of calcium ions (Ca2+) homeostasis induced by misfolded tau and β-amyloid plays an important role in the progressive neuronal loss occurring in specific areas of the brain. In addition to the control of bioenergetics and ROS production, mitochondria are fine regulators of the cytosolic Ca2+ homeostasis that induce vital signalling mechanisms in excitable cells such as neurons. Impairment in the mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) or release through the Na+/Ca2+ exchanger may lead to mitochondrial Ca2+ overload and opening of the permeability transition pore inducing neuronal death. Recent evidence suggests an important role for these mechanisms as the underlying causes for neuronal death in β-amyloid and tau pathology. The present review will focus on the mechanisms that lead to cytosolic and especially mitochondrial Ca2+ disturbances occurring in AD and tau-induced FTD, and propose possible therapeutic interventions for these disorders.

A Protective Role of Translocator Protein in Alzheimer’s Disease Brain

2020 ◽  
Vol 17 (1) ◽  
pp. 3-15 ◽  
Author(s):  
Marianna E. Jung
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Permeability Transition ◽  
Neuronal Degeneration ◽  
Mitochondrial Protein ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Protective Role ◽  
Translocator Protein ◽  
Initial Increase

Translocator Protein (18 kDa) (TSPO) is a mitochondrial protein that locates cytosol cholesterol to mitochondrial membranes to begin the synthesis of steroids including neurotrophic neurosteroids. TSPO is abundantly present in glial cells that support neurons and respond to neuroinflammation. Located at the outer membrane of mitochondria, TSPO regulates the opening of mitochondrial permeability transition pore (mPTP) that controls the entry of molecules necessary for mitochondrial function. TSPO is linked to neurodegenerative Alzheimer’s Disease (AD) such that TSPO is upregulated in the brain of AD patients and signals AD-induced adverse changes in brain. The initial increase in TSPO in response to brain insults remains elevated to repair cellular damages and perhaps to prevent further neuronal degeneration as AD progresses. To exert such protective activities, TSPO increases the synthesis of neuroprotective steroids, decreases neuroinflammation, limits the opening of mPTP, and reduces the generation of reactive oxygen species. The beneficial effects of TSPO on AD brain are manifested as the attenuation of neurotoxic amyloid β and mitochondrial dysfunction accompanied by the improvement of memory and cognition. However, the protective activities of TSPO appear to be temporary and eventually diminish as the severity of AD becomes profound. Timely treatment with TSPO agonists/ligands before the loss of endogenous TSPO’s activity may promote the protective functions and may extend neuronal survival.

scholarly journals A novel estrogen receptor GPER inhibits mitochondria permeability transition pore opening and protects the heart against ischemia-reperfusion injury

2010 ◽  
Vol 298 (1) ◽  
pp. H16-H23 ◽  
Author(s):  
Jean Chrisostome Bopassa ◽  
Mansoureh Eghbali ◽  
Ligia Toro ◽  
Enrico Stefani
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Rate Pressure Product ◽  
Triphenyltetrazolium Chloride ◽  
Mptp Opening ◽  
Mitochondria Permeability Transition Pore

Several studies have recently demonstrated that G protein-coupled receptor 30 (GPER) can directly bind to estrogen and mediate its action. We investigated the role and the mechanism of estrogen-induced cardioprotection after ischemia-reperfusion using a specific GPER agonist G1. Isolated hearts from male mice were perfused using Langendorff technique with oxygenated (95% O2 and 5% CO2) Krebs Henseleit buffer (control), with G1 (1 μM), and G1 (1 μM) together with extracellular signal-regulated kinase (Erk) inhibitor PD-98059 (5μM). After 20 min of perfusion, hearts were subjected to 20 min global normothermic (37°C) ischemia followed by 40 min reperfusion. Cardiac function was measured, and myocardial necrosis was evaluated by triphenyltetrazolium chloride staining at the end of the reperfusion. Mitochondria were isolated after 10 min of reperfusion to assess the Ca2+ load required to induce mitochondria permeability transition pore (mPTP) opening. G1-treated hearts developed better functional recovery with higher rate pressure product (RPP, 6140 ± 264 vs. 2,640 ± 334 beats·mmHg−1·min−1, P < 0.05). The infarct size decreased significantly in G1-treated hearts (21 ± 2 vs. 46 ± 3%, P < 0.001), and the Ca2+ load required to induce mPTP opening increased (2.4 ± 0.06 vs. 1.6 ± 0.11 μM/mg mitochondrial protein, P < 0.05) compared with the controls. The protective effect of G1 was abolished in the presence of PD-98059 [RPP: 4,120 ± 46 beats·mmHg−1·min−1, infarct size: 53 ± 2%, and Ca2+ retention capacity: 1.4 ± 0.11 μM/mg mitochondrial protein ( P < 0.05)]. These results suggest that GPER activation provides a cardioprotective effect after ischemia-reperfusion by inhibiting the mPTP opening, and this effect is mediated by the Erk pathway.

scholarly journals Post-ischemic Myocardial Inflammatory Response: A Complex and Dynamic Process Susceptible to Immunomodulatory Therapies

2021 ◽  
Vol 8 ◽  
Author(s):  
Niek J. Pluijmert ◽  
Douwe E. Atsma ◽  
Paul H. A. Quax
Keyword(s):  
Heart Failure ◽  
Myocardial Ischemia ◽  
Inflammatory Response ◽  
Cell Damage ◽  
Ischemia Reperfusion ◽  
Inflammatory Cells ◽  
Therapeutic Interventions ◽  
Developing Heart ◽  
Myocardial Ischemia Reperfusion ◽  
Immunomodulatory Therapies

Following acute occlusion of a coronary artery causing myocardial ischemia and implementing first-line treatment involving rapid reperfusion, a dynamic and balanced inflammatory response is initiated to repair and remove damaged cells. Paradoxically, restoration of myocardial blood flow exacerbates cell damage as a result of myocardial ischemia–reperfusion (MI-R) injury, which eventually provokes accelerated apoptosis. In the end, the infarct size still corresponds to the subsequent risk of developing heart failure. Therefore, true understanding of the mechanisms regarding MI-R injury, and its contribution to cell damage and cell death, are of the utmost importance in the search for successful therapeutic interventions to finally prevent the onset of heart failure. This review focuses on the role of innate immunity, chemokines, cytokines, and inflammatory cells in all three overlapping phases following experimental, mainly murine, MI-R injury known as the inflammatory, reparative, and maturation phase. It provides a complete state-of-the-art overview including most current research of all post-ischemic processes and phases and additionally summarizes the use of immunomodulatory therapies translated into clinical practice.

scholarly journals Ferroptosis and Acetaminophen Hepatotoxicity – Are We Going Down Another Rabbit Hole?

2021 ◽  
Author(s):  
Hartmut Jaeschke ◽  
Olamide B Adelusi ◽  
Anup Ramachandran
Keyword(s):  
Cell Death ◽  
Intracellular Signaling ◽  
Oxidant Stress ◽  
Reactive Oxygen ◽  
Permeability Transition ◽  
Mitogen Activated Protein Kinase ◽  
Glutathione Depletion ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Apap Hepatotoxicity

Acetaminophen (APAP) hepatotoxicity is the most frequent cause of acute liver failure in the US. The mechanisms of APAP-induced liver injury have been under extensive investigations for decades and many key events of this necrotic cell death are known today. Initially, two opposing hypotheses for cell death were proposed: Reactive metabolite and protein adducts formation versus reactive oxygen and lipid peroxidation (LPO). In the end, both mechanisms were reconciled, and it is now generally accepted that the toxicity starts with formation of reactive metabolites which, after glutathione depletion, bind to cellular proteins, especially on mitochondria. This results in a mitochondrial oxidant stress, which requires amplification through a mitogen activated protein kinase cascade leading ultimately to enough reactive oxygen and peroxynitrite formation to trigger the mitochondrial membrane permeability transition and cell death. However, the earlier rejected LPO hypothesis seems to make a come-back recently under a different name: ferroptosis. Therefore, the objective of this review was to critically evaluate the available information about intracellular signaling mechanisms of APAP-induced cell death and those of ferroptosis. Conclusion: Under pathophysiologically relevant conditions, there is no evidence for quantitatively enough LPO to cause cell death and thus APAP hepatotoxicity is not caused by ferroptosis. However, the role of mitochondria localized minor LPO remains to be further investigated.

Abstract 359: Higher ROS Generation and Lower Threshold of mPTP Opening May Underlie Increased Vulnerability of Late Pregnant Heart to Ischemia-Reperfusion Injury

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Jingyuan Li ◽  
Andrea Iorga ◽  
Ji-Youn Youn ◽  
Hua Cai ◽  
Vera Regitz-Zagrosek ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ros Generation ◽  
Hemodynamic Parameters ◽  
Mptp Opening

Although the murine late pregnant (LP) heart is speculated to be a better functioning heart during physiological conditions, the susceptibility of LP hearts to I/R injury is still unknown. The aims of this study were to investigate the cardiac vulnerability of LP rodents to ischemia/reperfusion (I/R) injury and to explore its underlying mechanisms. In-vivo female rat hearts (non-pregnant (NP) or LP) or Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion. The infarct size was ∼4 fold larger in LP compared to NP both in the in-vivo rat model and ex-vivo mouse model. The hemodynamic parameters were similar between NP and LP before ischemia. However, the postischemic functional recovery was extremely poor in LP mice comparing to NP mice. RPP was reduced from 12818±1213mmHg*beats/min in NP to 1617± 287mmHg*beats/min in LP mice at the end of reperfusion. Interestingly, all of the hemodynamic parameters almost fully recovered in hearts seven days post-partum (PP7)( RPP= 9604±1215 mmHg*beats/min). To explore the mitochondrial function involvement in the higher vulnerability of LP hearts to I/R injury, mitochondrial respiration and ROS production were measured. Respiratory control index(RCI) were significantly decreased in LP subjected to I/R compared to NP and PP7 (RCI=1.9±0.1 in LP, 4.0±0.5 in NP and 3.9±0.5 in PP7, P<0.05 LP vs. NP and PP7). The superoxide production was also significantly higher in isolated cardiac mitochondria from LP hearts subjected to I/R injury (10.7±1.7mM/min/mg protein in NP; 21.3±3.1mM/min/mg protein in LP and 9.3±3.3mM/min/mg protein in PP7; p<0.05 LP vs. NP and PP7). The threshold for opening of mitochondrial permeability transition pore (mPTP) in response to Ca2+ overload was much lower in LP hearts (calcium retention capacity(CRC)=167±10 nmol/mg-mitochondrial protein) compared with NP (233±18 nmol/mg-mitochondrial protein) and PP7 (260±12 nmol/mg-mitochondrial protein, P<0.01). In conclusion, the higher susceptibility of LP hearts to I/R injury is associated with a lower threshold for triggering the mitochondrial permeability transition pore (mPTP) opening in response to Ca2+ overload which may at least be in part due to higher ROS generation and lower mitochondrial respiration.

scholarly journals The Injury and Therapy of Reactive Oxygen Species in Intracerebral Hemorrhage Looking at Mitochondria

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Jie Qu ◽  
Weixiang Chen ◽  
Rong Hu ◽  
Hua Feng
Keyword(s):  
Reactive Oxygen Species ◽  
Intracerebral Hemorrhage ◽  
Structural Damage ◽  
Mitochondrial Permeability Transition ◽  
Reactive Oxygen ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Inflammatory Cells ◽  
Oxygen Species ◽  
Major Health Problem

Intracerebral hemorrhage is an emerging major health problem often resulting in death or disability. Reactive oxygen species (ROS) have been identified as one of the major damaging factors in ischemic stroke. However, there is less discussion about ROS in hemorrhage stroke. Metabolic products of hemoglobin, excitatory amino acids, and inflammatory cells are all sources of ROS, and ROS harm the central nervous system through cell death and structural damage, especially disruption of the blood-brain barrier. We have considered the antioxidant system of the CNS itself and the drugs aiming to decrease ROS after ICH, and we find that mitochondria are key players in all of these aspects. Moreover, when the mitochondrial permeability transition pore opens, ROS-induced ROS release, which leads to extensive liberation of ROS and mitochondrial failure, occurs. Therefore, the mitochondrion may be a significant target for elucidating the problem of ROS in ICH; however, additional experimental support is required.

scholarly journals Low expression of ANT1 confers oncogenic properties to rhabdomyosarcoma tumor cells via modulating metabolism and death pathways

2020 ◽  
Author(s):  
J Vial ◽  
P Huchedé ◽  
S Fagault ◽  
F Basset ◽  
M Rossi ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Genetic Disorders ◽  
Mitochondrial Protein ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Bioinformatic Analysis ◽  
Metabolic Switch ◽  
Adp Release ◽  
Resistance To Stress ◽  
Mitochondria Permeability Transition Pore

ABSTRACTRhabdomyosarcoma (RMS) is the most frequent form of pediatric soft-tissue sarcoma. It is divided into 2 main subtypes: ERMS (embryonal) and ARMS (alveolar). Current treatments are based on chemotherapy, surgery and radiotherapy. 5-year survival rate remains of 70% since 2000, despite several clinical trials.RMS cells are thought to derive from muscle lineage precursors. During development, myogenesis is characterized by primary expansion of myoblasts, elimination of those in excess by cell death and the differentiation of the remaining ones into myotubes and myofibers. The idea that these processes could be hijacked by tumor cells to sustain their oncogenic transformation has emerged, while RMS is being considered as the Mister Hyde’s side of myogenesis. Thus, focusing on myogenic developmental programs could help understanding RMS molecular aetiology.Following this idea, we decided to concentrate on ANT1, which is involved in myogenesis and is the underlying cause of genetic disorders associated with muscle degeneration. ANT1 is a mitochondrial protein, which has a functional duality, as it is involved both in metabolism via regulation of ATP/ADP release from mitochondria, but also in apoptosis as part as the mitochondria Permeability Transition Pore (mPTP). By bioinformatic analysis of transcriptomic datasets, we observed that ANT1 is expressed at low levels in RMS. Using CRISPR-Cas9 technology, we showed that decreased ANT1 expression confers selective advantages to RMS cells in terms of proliferation and resistance to stress-induced death. These effects result notably from a metabolic switch. Restoration of ANT1 expression using a Tet-On system is sufficient to prime tumor cells to death and to increase their sensitivity to chemotherapies. Thus, modulation of ANT1 activity could appear as an appealing therapeutic approach in RMS management.

Abstract 389: Alterations of Mitochondrial Calcium Handling in Heart Failure

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
An-Chi Wei ◽  
Ting Liu ◽  
Brian O’Rourke
Keyword(s):  
Heart Failure ◽  
Contractile Function ◽  
Critical Role ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Therapeutic Interventions ◽  
Calcium Handling ◽  
Aortic Constriction ◽  
Cardiac Contractile Function

Heart failure (HF) and sudden cardiac death (SCD) are major public health concerns that are increasing in incidence, yet the mechanisms underlying SCD in patients with HF are poorly understood. In a novel guinea pig model of HF/SCD, we showed that in vivo treatment with a mitochondrial Na+/Ca2+ exchanger (mNCE) inhibitor attenuates cardiac remodeling, preserves cardiac contractile function, and improves survival, supporting a critical role for altered mitochondrial Ca2+ dynamics in the pathophysiology. Here, we investigate whether the intrinsic mitochondrial Ca2+ transport rates are altered in this HF model. Methods: Ascending aortic constriction, combined with daily i.p. injection of isoproterenol (ISO), were used to induce HF (ACi) with acquired long QT. This group was compared with animals subjected to aortic constriction alone (AC), or sham-operated animals with (SHAMi) or without (SHAM) ISO treatment. Ca2+ Green-5N was used to measure total mitochondrial Ca2+ uptake and to quantify mitochondrial Ca2+ influx and efflux rates in isolated cardiac mitochondria. Results: Both the total mitochondrial Ca2+ load and the Ca2+ capacity prior to triggering permeability transition pore (mPTP) opening were reduced in HF mitochondria (5mM NaCl present). Mitochondrial Ca2+ fluxes, individually measured with sequential additions of 15μM free Ca2+, 10nM Ru360 and 5mM NaCl, showed that initial Ca2+ uptake rate through the mitochondrial Ca2+ uniporter (mCU: 0.55 nmol/sec/mg) was not significantly changed in HF; however, the Ca2+ extrusion rate through mNCE was larger in HF (AC:0.022 nmol/sec/mg; SHAM:0.018; ACi:0.013; SHAMi:0.009), but with a lower affinity for Na+. Interestingly, Na+-independent efflux via mPTP increased in HF (AC:0.0040 nmol/sec/mg; SHAM:0.0022; ACi:0.0013; SHAMi:0.012). Mitochondria from failing hearts also showed decreased respiration and increased ROS emission. Conclusions: The data indicate that an increase of intrinsic Ca2+ efflux and the increase in cytoplasmic Na+ in HF could both contribute to blunted mitochondrial Ca2+ in HF, which will affect cardiac energetics and ROS balance. Inhibitors of mNCE or mPTP are thus proposed to be therapeutic interventions that would improve mitochondrial Ca2+ balance and function in HF.

Sign in / Sign up

Export Citation Format

Share Document