1,721,878 research outputs found
Modulation of the Mitochondrial Cyclosporin A-Sensitive Permeability Transition Pore by the Proton Electrochemical Gradient. Evidence that the Pore can be Opened by Membrane Depolarization
No full textThis paper reports an investigation on the relationship between the proton electrochemical gradient (delta mu H+) and the cyclosporin A-sensitive permeability transition pore (PTP) in rat liver mitochondria. Using the SH group cross-linker phenylarsine oxide as the inducer, we show that both matrix pH and the membrane potential can modulate the process of PTP induction independently of Ca2+. We find that membrane depolarization induces the PTP per se when pHi is above 7.0, while at acidic matrix pH values PTP induction is effectively prevented. Since Ca2+ uptake leads to major modifications of the delta mu H+ (i.e. matrix alkalinization and membrane depolarization), we have explored the possibility that the Ca(2+)-induced changes of the delta mu H+ may contribute to PTP induction by Ca2+. Our data in mitochondria treated with Ca2+ plus N-ethylmaleimide and Ca2+ plus phosphate show that membrane depolarization is a powerful inducer of the PTP. Taken together, our observations indicate that the PTP can be controlled directly by the delta mu H+ both in the absence and presence of Ca2+, and suggest that a collapse of the membrane potential may be the cause rather than the consequence of PTP induction under many experimental conditions. Thus, many inducers may converge on dissipation of the membrane potential component of the delta mu H+ by a variety of mechanisms
Looking Back to the Future of Mitochondrial Research
Full text link–ethos anthropoi daimon—is a famous aphorismof theGreek philosopher
Heraclitus (544–483 BC). While its deeper meaning is probably more complex, the conventional
translation is “a human being’s character is his/her fate.” When I was asked by George Billman to
contribute my thoughts on the future of mitochondrial research it occurred to me that perhaps I
could try to foretell the fate of mitochondrial research from its character, i.e., from the key themes
from which the discipline developed. I will limit this brief comment to a few topics that also
reflect my own interests, and that should not be considered even an attempt to be exhaustive.
In the twentieth century the key issue in Bioenergetics (hence in mitochondrial research) has
been the mechanism of energy conservation. The turning point was the proposal and then the
demonstration of Peter Mitchell’s chemiosmotic hypothesis, i.e., that in mitochondria the basic
events are the coupling of aerobic electron transfer to H+ pumping, the formation of the H+
electrochemical gradient and its harnessing by the ATP synthase (Mitchell, 1966), reprinted
in Mitchell (2011). It is remarkable that the most recent advances in structural biology and
superresolution microscopy, which are removing hurdles and moving the boundaries of Science
beyond imagination, have confirmed the basic tenets of chemiosmotic principles in amazing detail
The Permeability Transition Pore. Control Points of a Cyclosporin A-sensitive Mitochondrial Channel Involved in Cell Death
No full textThe permeability transition pore (MTP) is a high conductance channel of the mitochondrial inner membrane inhibited by cyclosporin A. While the physiological role of the MTP has not been clarified yet, it is becoming clear that this channel plays an important role in the pathways leading to cell death. The recent demonstrations that the MTP is controlled by the membrane potential, that a variety of physiological and pathological effectors can modulate the threshold voltage at which pore opening occurs, and that surface potential may contribute to pore modulation provide a useful framework to describe the mechanistic aspects of pore function in isolated mitochondria. Here we (i) briefly review the key features of pore regulation, and report our recent progress on the role of oxidants and mitochondrial cyclophilin; and (ii) elaborate on how MTP regulation by cellular pathophysiological effectors (such as cytosolic [Ca2+] transients, oxidative stress, and changes in the concentration of polyamines, nitric oxide, and metabolites of both the sphingomyelin and phospholipase A2 pathways) might take place in vivo. Further definition of the MTP checkpoints should help in the design of specific modulators, and offers great promise for the development of new conceptual and pharmacological tools aimed at therapeutic intervention in pathological conditions where pore opening is a critical event
Mitochondria in muscle cell death
No full textMitochondria, the main source of energy for eukaryotic cells through oxidative phosphorylation, also play a key role in the pathways to cell death. The mode of cell death may be influenced by the availability of ATP, and its very occurrence may critically depend on release of mitochondrial proteins like cytochrome c, apoptosis-inducing factor and possibly caspases 3 and 9. Ca2+-dependent onset of the permeability transition, caused by opening of a cyclosporin A-sensitive pore modulated by cyclophilin D, may play a major role in cell death through ATP depletion, disruption of Ca2+ homeostasis, and release of specific mitochondrial proteins. Dysregulation of Ca2+ homeostasis, proteolysis and a decreased ability to cope with oxidative stress are involved in the pathogenesis of Duchenne's muscular dystrophy downstream of the genetic lesion, and mitochondria appear as likely targets that may amplify the initial insult resulting in the irreversible events leading to cell demise. My colleagues and I are studying the permeability transition in skeletal muscle mitochondria, and we are validating bupivacaine in a short-term model of muscle cell toxicity involving mitochondrial depolarization and pore opening as early events. Specific goals for the future are to further define the role of mitochondria in muscle cell death, with particular emphasis on the role of the permeability transition pore and cyclophilin D, and to develop and test drugs able to affect its course in model systems in vitro and in the mdx mouse, an animal model of Duchenne's muscular dystrophy
Modulation of Ca2+ Efflux and Rebounding Ca2+ Transport in Rat Liver Mitochondria
No full textThe paper analyzes the factors affecting the H+-K+ exchange catalyzed by rat liver mitochondria depleted of endogenous Mg2+ by treatment with the ionophore A23187. The exchange has been monitored as the rate of K+ efflux following addition of A23187 in low-K+ media. (1) The H+-K+ exchange is abolished by uncouplers and respiratory inhibitors. The inhibition is not related to the depression of ΔpH, whereas a dependence is found on the magnitude of the transmembrane electrical potential, Δψ. Maximal rate of K+ efflux is observed at 180–190 mV, whereas K+ efflux is inhibited below 140–150 mV. (2) Activation of H+-K+ exchange leads to depression of ΔpH but not of Δψ. Respiration is only slightly stimulated by the onset of H+-K+ exchange in the absence of valinomycin. These findings indicate that the exchange is electroneutral, and that the Δψ control presumably involves conformational changes of the carrier. (3) Incubation in hypotonic media at pH 7.4 or in isotonic media at alkaline pH results in a marked activation of the rate of H+-K+ exchange, while leaving unaffected the level of Mg2+ depletion. This type of activation results in partial ‘uncoupling’ from the Δψ control, suggesting that membrane stretching and alkaline pH induce conformational changes on the exchange carrier equivalent to those induced by high Δψ. (4) The available evidence suggests that the activity of the H+-K+ exchanger is modulated by the electrical field across the inner mitochondrial membrane
Perspectives in mitochondrial research. Foreword
No full textI would like to express my appreciation to Angelo Azzi and to the Board of IUBMB Life for the initiative of a Special Issue
on Mitochondria. In recent years we have witnessed a spectacular increase in the scope and impact of mitochondrial research beyond Bioenergetics and well into Cell Biology, Oncology, Immunology, Toxicology, Neurology and Cardiology. This is largely due to new discoveries on the pathophysiological role of mitochondria in cell death, and to the increasing awareness that mitochondria are mechanistically involved in a variety of diseases and in the aging and apoptotic processes. This renewed interest is reshaping the traditional boundaries of mitochondrial science, and this series of reviews is meant to provide a perspective for future studies
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