Acetaminophen (APAP)-induced liver injury is an important clinical and toxicological problem. Understanding the mechanisms and modes of cell death are vital for the development of therapeutic ...interventions. The histological and clinical features of APAP hepatotoxicity including cell and organelle swelling, karyolysis, and extensive cell contents release lead to the characterization of the cell death as oncotic necrosis. However, the more recent identification of detailed signaling mechanisms of mitochondrial dysfunction, the amplification mechanisms of mitochondrial oxidant stress and peroxynitrite formation by a mitogen-activated protein kinase cascade, mechanisms of the mitochondrial permeability transition pore opening and nuclear DNA fragmentation as well as the characterization of the sterile inflammatory response suggested that the mode of cell death is better termed programmed necrosis. Additional features like mitochondrial Bax translocation and cytochrome c release, mobilization of lysosomal iron and the activation of receptor-interacting protein kinases and the inflammasome raised the question whether other emerging modes of cell death such as apoptosis, necroptosis, ferroptosis and pyroptosis could also play a role. The current review summarizes the key mechanisms of APAP-induced liver injury and compares these with key features of the newly described modes of cell death. Based on the preponderance of experimental and clinical evidence, the mode of APAP-induced cell death should be termed programmed necrosis; despite some overlap with other modes of cell death, APAP hepatotoxicity does not fulfill the characteristics of either apoptosis, necroptosis, ferroptosis, pyroptosis or autophagic cell death.
Abstract Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus ...critical for maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors Nix and Bnip3. In this review, we summarize our current knowledge on the mechanisms of mitophagy. We also discuss the pathophysiological roles of mitophagy and current assays used to monitor mitophagy.
The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is associated with both acute and ...chronic liver diseases with emerging evidence indicating that mitophagy, a selective form of autophagy for damaged/excessive mitochondria, plays a key role in the liver's physiology and pathophysiology. This review will focus on mitochondrial dynamics, mitophagy regulation, and their roles in various liver diseases (alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, hepatic ischemia-reperfusion injury, viral hepatitis, and cancer) with the hope that a better understanding of the molecular events and signaling pathways in mitophagy regulation will help identify promising targets for the future treatment of liver diseases.
Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in the USA and many other countries. Although the metabolism and pathogenesis of APAP has been extensively investigated ...for decades, the mechanisms by which APAP induces liver injury are incompletely known, which hampers the development of effective therapeutic approaches to tackle this important clinical problem. Autophagy is a highly conserved intracellular degradation pathway, which aims at recycling cellular components and damaged organelles in response to adverse environmental conditions and stresses as a survival mechanism. There is accumulating evidence indicating that autophagy is activated in response to APAP overdose in specific liver zone areas, and pharmacological activation of autophagy protects against APAP‐induced liver injury. Increasing evidence also suggests that hepatic autophagy is impaired in nonalcoholic fatty livers (NAFLD), and NAFLD patients are more susceptible to APAP‐induced liver injury. Here, we summarized the current progress on the role and mechanisms of autophagy in protecting against APAP‐induced liver injury.
Autophagy can selectively remove damaged organelles, including mitochondria, and, in turn, protect against mitochondria‐damage–induced cell death. Acetaminophen (APAP) overdose can cause liver injury ...in animals and humans by inducing mitochondria damage and subsequent necrosis in hepatocytes. Although many detrimental mechanisms have been reported to be responsible for APAP‐induced hepatotoxicity, it is not known whether APAP can modulate autophagy to regulate hepatotoxicity in hepatocytes. To test the hypothesis that autophagy may play a critical protective role against APAP‐induced hepatotoxicity, primary cultured mouse hepatocytes and green fluorescent protein/light chain 3 transgenic mice were treated with APAP. By using a series of morphological and biochemical autophagic flux assays, we found that APAP induced autophagy both in the in vivo mouse liver and in primary cultured hepatocytes. We also found that APAP treatment might suppress mammalian target of rapamycin in hepatocytes and that APAP‐induced autophagy was suppressed by N‐acetylcysteine, suggesting APAP mitochondrial protein binding and the subsequent production of reactive oxygen species may play an important role in APAP‐induced autophagy. Pharmacological inhibition of autophagy by 3‐methyladenine or chloroquine further exacerbated APAP‐induced hepatotoxicity. In contrast, induction of autophagy by rapamycin inhibited APAP‐induced hepatotoxicity. Conclusion: APAP overdose induces autophagy, which attenuates APAP‐induced liver cell death by removing damaged mitochondria. (HEPATOLOGY 2012)
In 2012, we briefly summarized the mechanisms, pathophysiological roles and methods for analyzing mitophagy. As then, the mitophagy field has continued to grow rapidly, and many new molecular ...mechanisms regulating mitophagy and molecular tools for monitoring mitophagy have been discovered and developed. Therefore, the purpose of this review is to update information regarding these advances in mitophagy while focusing on basic molecular mechanisms of mitophagy in different organisms and its pathophysiological roles. We also discuss the advantage and limitations of current methods to monitor and quantify mitophagy in cultured cells and in vivo mouse tissues.
Mitochondria are cellular energy powerhouses that play important roles in maintaining cell survival, cell death and cellular metabolic homeostasis. Timely removal of damaged mitochondria via ...autophagy (mitophagy) is thus critical for cellular homeostasis and function. Mitochondria are reticular organelles that have high plasticity for their dynamic structures and constantly undergo fission and fusion as well as movement through the cytoskeleton. In this review, we discuss the most recent progress on the molecular mechanisms and roles of mitochondrial fission/fusion and mitochondrial motility in mitophagy. We also discuss multiple pathways leading to the quality control of mitochondria in addition to the traditional mitophagy pathway under different conditions.
Alcoholic liver disease (ALD) is a major health problem in the United States and worldwide without successful treatments. Chronic alcohol consumption can lead to ALD, which is characterized by ...steatosis, inflammation, fibrosis, cirrhosis, and even liver cancer. Recent studies suggest that alcohol induces both cell death and adaptive cell survival pathways in the liver, and the balance of cell death and cell survival ultimately decides the pathogenesis of ALD. This review summarizes the recent progress on the role and mechanisms of apoptosis, necroptosis, and autophagy in the pathogenesis of ALD. Understanding the complex regulation of apoptosis, necrosis, and autophagy may help to develop novel therapeutic strategies by targeting all 3 pathways simultaneously.
Cell death and cell survival are closely associated with alcoholic liver disease.
Ethanol metabolism leads to increased oxidative stress resulting in mitochondrial damage and apoptosis in hepatocytes.
Chronic alcohol consumption increases gut permeability and elevated systemic levels of gut‐derived endotoxins resulting in increased production of TNF‐α from activated Kupffer cells.
Depending on the cIAP levels and caspase‐8 activation in hepatocytes, TNF‐α either induces apoptosis or necroptosis by activating Bid‐mediated mitochondrial apoptotic pathway or ripoptosome or necrosome.
Acetaminophen (APAP) overdose is one of the leading causes of hepatotoxicity and acute liver failure in the United States. Accumulating evidence suggests that hepatocyte necrosis plays a critical ...role in APAP‐induced liver injury (AILI). However, the mechanisms of APAP‐induced necrosis and liver injury are not fully understood. In this study, we found that p53 up‐regulated modulator of apoptosis (PUMA), a B‐cell lymphoma‐2 (Bcl‐2) homology domain 3 (BH3)‐only Bcl‐2 family member, was markedly induced by APAP in mouse livers and in isolated human and mouse hepatocytes. PUMA deficiency suppressed APAP‐induced mitochondrial dysfunction and release of cell death factors from mitochondria, and protected against APAP‐induced hepatocyte necrosis and liver injury in mice. PUMA induction by APAP was p53 independent, and required receptor‐interacting protein kinase 1 (RIP1) and c‐Jun N‐terminal kinase (JNK) by transcriptional activation. Furthermore, a small‐molecule PUMA inhibitor, administered after APAP treatment, mitigated APAP‐induced hepatocyte necrosis and liver injury. Conclusion: Our results demonstrate that RIP1/JNK‐dependent PUMA induction mediates AILI by promoting hepatocyte mitochondrial dysfunction and necrosis, and suggest that PUMA inhibition is useful for alleviating acute hepatotoxicity attributed to APAP overdose.
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