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Biological & Pharmaceutical Bulletin 2015Loss of cardiac myocytes plays a critical role in the pathogenesis of cardiovascular disorders. A decrease in the number of cardiac myocytes in cardiac diseases results... (Review)
Review
Loss of cardiac myocytes plays a critical role in the pathogenesis of cardiovascular disorders. A decrease in the number of cardiac myocytes in cardiac diseases results in sustained, irreversible contractile failure of myocardium. Therefore prevention of cardiac cell death is a potential therapeutic strategy for various heart diseases. It is well accepted that three types of phenomena such as apoptosis, necrosis, and autophagy may be involved in myocardial cell death. Apoptosis is a highly regulated process that is promoted via death receptor pathway in the plasma membrane or via mitochondrial pathway. Necrosis is induced via mitochondrial swelling, cell rupture, and subsequent inflammation. Autophagy is a cell survival mechanism that involves degradation and recycling of cytoplasmic components. As compared with the other two mechanisms, autophagy may mediate cell death under specific conditions. These three types of cell death in the myocardium are discussed in this article.
Topics: Apoptosis; Autophagy; Cell Death; Cell Survival; Heart Diseases; Humans; Myocardium; Myocytes, Cardiac; Necrosis
PubMed: 26235571
DOI: 10.1248/bpb.b15-00288 -
Mitochondrion Jan 2018Mitochondria are critical players involved in both cell life and death through multiple pathways. Structural integrity, metabolism and function of mitochondria are... (Review)
Review
Mitochondria are critical players involved in both cell life and death through multiple pathways. Structural integrity, metabolism and function of mitochondria are regulated by matrix volume due to physiological changes of ion homeostasis in cellular cytoplasm and mitochondria. Ca and K presumably play a critical role in physiological and pathological swelling of mitochondria when increased uptake (influx)/decreased release (efflux) of these ions enhances osmotic pressure accompanied by high water accumulation in the matrix. Changes in the matrix volume in the physiological range have a stimulatory effect on electron transfer chain and oxidative phosphorylation to satisfy metabolic requirements of the cell. However, excessive matrix swelling associated with the sustained opening of mitochondrial permeability transition pores (PTP) and other PTP-independent mechanisms compromises mitochondrial function and integrity leading to cell death. The mechanisms of transition from reversible (physiological) to irreversible (pathological) swelling of mitochondria remain unknown. Mitochondrial swelling is involved in the pathogenesis of many human diseases such as neurodegenerative and cardiovascular diseases. Therefore, modeling analysis of the swelling process is important for understanding the mechanisms of cell dysfunction. This review attempts to describe the role of mitochondrial swelling in cell life and death and the main mechanisms involved in the maintenance of ion homeostasis and swelling. The review also summarizes and discusses different kinetic models and approaches that can be useful for the development of new models for better simulation and prediction of in vivo mitochondrial swelling.
Topics: Cardiovascular Diseases; Electron Transport; Humans; Mitochondria; Mitochondrial Membranes; Mitochondrial Swelling; Models, Biological; Neurodegenerative Diseases; Osmotic Pressure; Oxidative Phosphorylation; Permeability
PubMed: 28802667
DOI: 10.1016/j.mito.2017.08.004 -
Journal of Visualized Experiments : JoVE May 2018The production of ATP by oxidative phosphorylation is the primary function of mitochondria. Mitochondria in higher eukaryotes also participate in cytosolic Ca buffering,...
The production of ATP by oxidative phosphorylation is the primary function of mitochondria. Mitochondria in higher eukaryotes also participate in cytosolic Ca buffering, and the ATP production in mitochondrial can be mediated by intramitochondrial free Ca concentration. Ca retention capacity can be regarded as the capability of mitochondria to retain calcium in the mitochondrial matrix. Accumulated intracellular Ca leads to the permeability of the inner mitochondrial membrane, termed the opening of mitochondrial permeability transition pore (mPTP), which leads to the leakage of molecules with a molecular weight less than 1.5 kDa. Ca-triggered mitochondria swelling is used to indicate the mPTP opening. Here, we describe two assays to examine the Ca retention capacity and Ca-triggered mitochondrial swelling in isolated mitochondria. After certain amounts of Ca are added, all steps can be completed in one day and recorded by a microplate reader. Thus, these two simple and effective assays can be adopted to assess the Ca-related mitochondrial functions.
Topics: Biological Assay; Calcium; Humans; Mitochondrial Swelling; Protein Biosynthesis
PubMed: 29781984
DOI: 10.3791/56236 -
Basic Research in Cardiology Sep 2023Giant mitochondria are frequently observed in different disease models within the brain, kidney, and liver. In cardiac muscle, these enlarged organelles are present... (Review)
Review
Giant mitochondria are frequently observed in different disease models within the brain, kidney, and liver. In cardiac muscle, these enlarged organelles are present across diverse physiological and pathophysiological conditions including in ageing and exercise, and clinically in alcohol-induced heart disease and various cardiomyopathies. This mitochondrial aberration is widely considered an early structural hallmark of disease leading to adverse organ function. In this thematic paper, we discuss the current state-of-knowledge on the presence, structure and functional implications of giant mitochondria in heart muscle. Despite its demonstrated reoccurrence in different heart diseases, the literature on this pathophysiological phenomenon remains relatively sparse since its initial observations in the early 60s. We review historical and contemporary investigations from cultured cardiomyocytes to human tissue samples to address the role of giant mitochondria in cardiac health and disease. Finally, we discuss their significance for the future development of novel mitochondria-targeted therapies to improve cardiac metabolism and functionality.
Topics: Humans; Myocytes, Cardiac; Mitochondrial Swelling; Mitochondria; Cardiomyopathies; Myocardium; Mitochondria, Heart
PubMed: 37775647
DOI: 10.1007/s00395-023-01011-3 -
Archives of Biochemistry and Biophysics May 2022Mitochondria change their morphology and inner membrane structure depending on their activity. Since mitochondrial activity also depends on their structure, it is...
Mitochondria change their morphology and inner membrane structure depending on their activity. Since mitochondrial activity also depends on their structure, it is important to elucidate the interrelationship between the activity and structure of mitochondria. However, the mechanism by which mitochondrial activity affects the structure of cristae, the folded structure of the inner membrane, is not well understood. In this study, the effect of the mitochondrial activity on the cristae structure was investigated by examining the structural rigidity of cristae. Taking advantage of the fact that unfolding of cristae induces mitochondrial swelling, we investigated the relationship between mitochondrial activity and the susceptibility to swelling. The swelling of individual isolated mitochondria exposed to a hypotonic solution was observed with an optical microscope. The presence of respiratory substrates (malate and glutamate) increased the percentage of mitochondria that underwent swelling, and the further addition of rotenone or KCN (inhibitors of proton pumps) reversed the increase. In the absence of respiratory substrates, acidification of the buffer surrounding the mitochondria also increased the percentage of swollen mitochondria. These observations suggest that acidification of the outer surface of inner membranes, especially intracristal space, by proton translocation from the matrix to the intracristal space, decreases the structural rigidity of the cristae. This interpretation was verified by the observation that ADP or CCCP, which induces proton re-entry to the matrix, suppressed the mitochondrial swelling in the presence of respiratory substrates. The addition of CCCP to the cells induced a morphological change in mitochondria from an initial elongated structure to a largely curved structure at pH 7.4, but there were no morphological changes when the pH of the cytosol dropped to 6.2. These results suggest that a low pH in the intracristal space may be helpful in maintaining the elongated structure of mitochondria. The present study shows that proton pumping by the electron transfer chain is the mechanism underlying mitochondrial morphology and the flexibility of cristae structure.
Topics: Carbonyl Cyanide m-Chlorophenyl Hydrazone; Mitochondria; Mitochondrial Membranes; Proton Pumps; Protons
PubMed: 35276212
DOI: 10.1016/j.abb.2022.109172 -
Biochimica Et Biophysica Acta.... Oct 2022Plant mitochondria are sensitive organelles affected by changing environmental stressors. Upon heat shock or the presence of reactive oxygen species, plant mitochondria... (Review)
Review
Plant mitochondria are sensitive organelles affected by changing environmental stressors. Upon heat shock or the presence of reactive oxygen species, plant mitochondria undergo in vivo morphological derangements associated with the extensively characterized opening of the mitochondrial permeability transition pore. Nevertheless, the classic mitochondrial permeability transition is known to be triggered by calcium overload causing mitochondrial swelling and dysfunction. Here we review evidence concerning calcium handling, permeability transition and mitochondrial impairments in plants, supporting the notion that the mitochondrial morphology transition is an in vivo indicator of the permeability transition.
Topics: Calcium; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Permeability
PubMed: 35772521
DOI: 10.1016/j.bbabio.2022.148586 -
Cells Feb 2019Thirty-five years ago, we described fragmentation of the mitochondrial population in a living cell into small vesicles (mitochondrial fission). Subsequently, this... (Review)
Review
Thirty-five years ago, we described fragmentation of the mitochondrial population in a living cell into small vesicles (mitochondrial fission). Subsequently, this phenomenon has become an object of general interest due to its involvement in the process of oxidative stress-related cell death and having high relevance to the incidence of a pathological phenotype. Tentatively, the key component of mitochondrial fission process is segregation and further asymmetric separation of a mitochondrial body yielding healthy (normally functioning) and impaired (incapable to function in a normal way) organelles with subsequent decomposition and removal of impaired elements through autophagy (mitophagy). We speculate that mitochondria contain cytoskeletal elements, which maintain the mitochondrial shape, and also are involved in the process of intramitochondrial segregation of waste products. We suggest that perturbation of the mitochondrial fission/fusion machinery and slowdown of the removal process of nonfunctional mitochondrial structures led to the increase of the proportion of impaired mitochondrial elements. When the concentration of malfunctioning mitochondria reaches a certain threshold, this can lead to various pathologies, including aging. Overall, we suggest a process of mitochondrial fission to be an essential component of a complex system controlling a healthy cell phenotype. The role of reactive oxygen species in mitochondrial fission is discussed.
Topics: Animals; Humans; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Dynamics; Mitochondrial Swelling; Models, Biological; Reactive Oxygen Species
PubMed: 30791381
DOI: 10.3390/cells8020175 -
JHEP Reports : Innovation in Hepatology Nov 2023Mitochondrial permeability transition pore (mPTP) opening is critical for mediating cell death during hepatic ischaemia-reperfusion injury (IRI). Blocking mPTP opening...
BACKGROUND & AIMS
Mitochondrial permeability transition pore (mPTP) opening is critical for mediating cell death during hepatic ischaemia-reperfusion injury (IRI). Blocking mPTP opening by inhibiting cyclophilin D (CypD) is a promising pharmacological approach for the treatment of IRI. Here, we show that diastereoisomers of a new class of small-molecule cyclophilin inhibitors (SMCypIs) have properties that make them attractive candidates for the development of therapeutic agents against liver IRI.
METHODS
Derivatives of the parent SMCypI were synthesised and evaluated for their ability to inhibit CypD peptidyl-prolyl - isomerase (PPIase) activity and for their mitoprotective properties, evaluated by measuring mitochondrial swelling and calcium retention capacity in liver mitochondria. The ability of the selected compounds to inhibit mPTP opening was evaluated in cells subjected to hypoxia/reoxygenation using a calcein/cobalt assay. Their ability to inhibit cell death was evaluated in cells subjected to hypoxia/reoxygenation by measuring lactate dehydrogenase (LDH) release, propidium iodide staining, and cell viability. The compound performing best was selected for efficacy evaluation in a mouse model of hepatic IRI.
RESULTS
The two compounds that showed the strongest inhibition of CypD PPIase activity and mPTP opening, C105 and C110, were selected. Their SR diastereoisomers carried the activity of the racemic mixture and exhibited mitoprotective properties superior to those of the known macrocyclic cyclophilin inhibitors cyclosporin A and alisporivir. C105SR was more potent than C110SR in inhibiting mPTP opening and prevented cell death in a model of hypoxia/reoxygenation. Finally, C105SR substantially protected against hepatic IRI by reducing hepatocyte necrosis and apoptosis.
CONCLUSIONS
We identified a novel cyclophilin inhibitor with strong mitoprotective properties both and that represents a promising candidate for cellular protection in hepatic IRI.
IMPACT AND IMPLICATIONS
Hepatic ischaemia-reperfusion injury (IRI) is one of the main causes of morbidity and mortality during or after liver surgery. However, no effective therapies are available to prevent or treat this devastating syndrome. An attractive strategy to prevent hepatic IRI aims at reducing cell death by targeting mitochondrial permeability transition pore opening, a phenomenon regulated by cyclophilin D. Here, we identified a new small-molecule cyclophilin inhibitor, and demonstrated the enhanced mitoprotective and hepatoprotective properties of one of its diastereoisomers both and , making it an attractive lead compound for subsequent clinical development.
PubMed: 37860051
DOI: 10.1016/j.jhepr.2023.100876 -
Journal of Biochemical and Molecular... Jul 2022Mitochondrial dysfunction and oxidative stress are identified to contribute to the mechanisms responsible for the pathogenesis of Alzheimer's disease (AD). Scopolamine...
Mitochondrial dysfunction and oxidative stress are identified to contribute to the mechanisms responsible for the pathogenesis of Alzheimer's disease (AD). Scopolamine (SCO) as a potent drug for inducing memory and learning impairment is associated with mitochondrial dysfunction and oxidative stress. In AD clinical trials molecules with antioxidant properties have shown modest benefit. Betanin as a multifunctional molecule with powerful antioxidative properties may be effective in the treatment of neurodegenerative. Hence, this study was designed to investigate the possible therapeutic effect of betanin against SCO-induced AD on Wistar rats. SCO (1 mg/kg) was administrated intraperitoneally to induce the AD in Wistar rats. The rats were treated with betanin doses (25 mg/kg and 50 mg/kg) intraperitoneally for 9 consecutive days. At the end of the 9th day, the animals were subjected to behavioral examination such as novel object recognition and passive avoidance tests and killed to study the mitochondrial and histological parameters. The results showed attenuation of SCO-induced memory and learning impairment by betanin at 50 mg/kg dose. Also, mitochondrial toxicity parameters such as mitochondrial membrane potential collapse, mitochondrial swelling, decreased activity of succinate dehydrogenase, and reactive oxygen species (ROS) production were reversed by betanin (50 mg/kg) compared to the SCO group. In addition, the ameliorative effect of betanin against SCO was demonstrated in histopathological results of hippocampus. The present investigation established that the betanin ameliorates the SCO-induced memory impairments, tissue injuries, and mitochondrial dysfunction by reducing mitochondrial ROS, which may be due to the potent antioxidant action of betanin.
Topics: Alzheimer Disease; Animals; Antioxidants; Betacyanins; Mitochondria; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Scopolamine
PubMed: 35411685
DOI: 10.1002/jbt.23076 -
Bio Systems Jul 2022Theoretical biophysical model is reported for mitochondrial swelling (MS) dynamics in vivo. This newly developed model is based on the detailed biophysical model of MS...
Theoretical biophysical model is reported for mitochondrial swelling (MS) dynamics in vivo. This newly developed model is based on the detailed biophysical model of MS dynamics in vitro, where mechanical properties of the inner mitochondrial membrane (IMM) were taken into account. The present model of MS dynamics in vivo is capable of analyzing MS dynamic transition from the reversible (physiological) to the irreversible (pathological) mode. This model was used to describe myocytes, assuming 1000 mitochondria distributed homogeneously over the sarcoplasm. Solute transport through the myocyte membrane was described by simplified phenomenological mechanisms of solute uptake and release. Biophysical processes occurring in mitochondria within cells were similar to those included in the earlier reported in vitro biophysical model of MS dynamics. Additionally, in vivo MS dynamics was simulated in different initial conditions, with results different from those of the in vitro model. Note that the presently reported model is the first attempt to develop a detailed biophysical model for the analysis of MS dynamics in vivo, capable of reproducing the transition between reversible and irreversible MS dynamics.
Topics: Biophysical Phenomena; Mitochondria; Mitochondrial Membranes; Mitochondrial Swelling
PubMed: 35413385
DOI: 10.1016/j.biosystems.2022.104679