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•Permeability transition pore (PTP) is a Ca2+-activated channel whose prolonged openings can lead to depolarization, Ca2+ release and cell death.•Our working hypothesis is that the ...channel forms from F-ATP synthase dimers following Ca2+-binding to the catalytic site.•Ca2+ competes with PTP-inhibitory Mg2+, and is an essential permissive factor for PTP opening.•Ca2+ binding could cause a conformational change transmitted via OSCP to the peripheral stalk and the the inner membrane.
Recent years have seen renewed interest in the permeability transition pore, a high conductance channel responsible for permeabilization of the inner mitochondrial membrane, a process that leads to depolarization and Ca2+ release. Transient openings may be involved in physiological Ca2+ homeostasis while long-lasting openings may trigger and/or execute cell death. In this review we specifically focus (i) on the hypothesis that the PTP forms from the F-ATP synthase and (ii) on the mechanisms through which Ca2+ can reversibly switch this energy-conserving nanomachine into an energy-dissipating device.
Abstract
The molecular identity of the mitochondrial megachannel (MMC)/permeability transition pore (PTP), a key effector of cell death, remains controversial. By combining highly purified, fully ...active bovine F-ATP synthase with preformed liposomes we show that Ca
2+
dissipates the H
+
gradient generated by ATP hydrolysis. After incorporation of the same preparation into planar lipid bilayers Ca
2+
elicits currents matching those of the MMC/PTP. Currents were fully reversible, were stabilized by benzodiazepine 423, a ligand of the OSCP subunit of F-ATP synthase that activates the MMC/PTP, and were inhibited by Mg
2+
and adenine nucleotides, which also inhibit the PTP. Channel activity was insensitive to inhibitors of the adenine nucleotide translocase (ANT) and of the voltage-dependent anion channel (VDAC). Native gel-purified oligomers and dimers, but not monomers, gave rise to channel activity. These findings resolve the long-standing mystery of the MMC/PTP and demonstrate that Ca
2+
can transform the energy-conserving F-ATP synthase into an energy-dissipating device.
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) targeting mitochondria are major causative factors in disease pathogenesis. The mitochondrial permeability transition pore (PTP) is a ...mega-channel modulated by calcium and ROS/RNS modifications and it has been described to play a crucial role in many pathophysiological events since prolonged channel opening causes cell death. The recent identification that dimers of ATP synthase form the PTP and the fact that posttranslational modifications caused by ROS/RNS also affect cellular bioenergetics through the modulation of ATP synthase catalysis reveal a dual function of these modifications in the cells. Here, we describe mitochondria as a major site of production and as a target of ROS/RNS and discuss the pathophysiological conditions in which oxidative and nitrosative modifications modulate the catalytic and pore-forming activities of ATP synthase.
The mitochondrial ATP synthase is a multi-subunit enzyme complex located in the inner mitochondrial membrane which is essential for oxidative phosphorylation under physiological conditions. In this ...review, we analyse the enzyme functions involved in cancer progression by dissecting specific conditions in which ATP synthase contributes to cancer development or metastasis. Moreover, we propose the role of ATP synthase in the formation of the permeability transition pore (PTP) as an additional mechanism which controls tumour cell death. We further describe transcriptional and translational modifications of the enzyme subunits and of the inhibitor protein IF1 that may promote adaptations leading to cancer metabolism. Finally, we outline ATP synthase gene mutations and epigenetic modifications associated with cancer development or drug resistance, with the aim of highlighting this enzyme complex as a potential novel target for future anti-cancer therapy.
Mitochondria are key organelles for brain health. Mitochondrial alterations have been reported in several neurodegenerative disorders, including Alzheimer’s disease (AD), and the comprehension of the ...underlying mechanisms appears crucial to understand their relationship with the pathology. Using multiple genetic, pharmacological, imaging, and biochemical approaches, we demonstrate that, in different familial AD cell models, mitochondrial ATP synthesis is affected. The defect depends on reduced mitochondrial pyruvate oxidation, due to both lower Ca2+-mediated stimulation of the Krebs cycle and dampened mitochondrial pyruvate uptake. Importantly, this latter event is linked to glycogen-synthase-kinase-3β (GSK-3β) hyper-activation, leading, in turn, to impaired recruitment of hexokinase 1 (HK1) to mitochondria, destabilization of mitochondrial-pyruvate-carrier (MPC) complexes, and decreased MPC2 protein levels. Remarkably, pharmacological GSK-3β inhibition in AD cells rescues MPC2 expression and improves mitochondrial ATP synthesis and respiration. The defective mitochondrial bioenergetics influences glutamate-induced neuronal excitotoxicity, thus representing a possible target for future therapeutic interventions.
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•Mitochondrial ATP synthesis is reduced in Alzheimer’s disease cell models•Lower mitochondrial Ca2+ signal and pyruvate uptake impair cell bioenergetics•GSK-3β reduces HK1-mitochondria association, destabilizing MPC complexes•The defective mitochondrial pyruvate flux alters neuronal function
Mitochondria are key organelles for brain health. Rossi et al. show that, in different Alzheimer’s disease cell models, lower mitochondrial Ca2+ signal and pyruvate uptake reduce ATP synthesis. GSK-3β hyper-activation contributes to the defect by impairing HK1-mitochondria association, decreasing MPC2 levels and destabilizing MPC complexes. Defective bioenergetics affects neuronal functionality.
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. NAFLD has emerged to be extremely prevalent, and predicted by obesity and male gender. It is ...defined by hepatic fat infiltration >5% hepatocytes, in the absence of other causes of liver pathology. It includes a spectrum of disease ranging from intrahepatic fat accumulation (steatosis) to various degrees of necrotic inflammation and fibrosis (non-alcoholic steatohepatatis NASH). NAFLD is associated, in children as in adults, with severe metabolic impairments, determining an increased risk of developing the metabolic syndrome. It can evolve to cirrhosis and hepatocellular carcinoma, with the consequent need for liver transplantation. Both genetic and environmental factors seem to be involved in the development and progression of the disease, but its physiopathology is not yet entirely clear. In view of this mounting epidemic phenomenon involving the youth, the study of NAFLD should be a priority for all health care systems. This review provides an overview of current and new clinical-histological concepts of pediatric NAFLD, going through possible implications into patho-physiolocical and therapeutic perspectives.
Digestive enzymes are able to break down proteins and carbohydrates and lipids, and their supplementation may play a role in the management of digestive disorders, from lactose intolerance to cystic ...fibrosis. To date, several formulations of digestive enzymes are available on the market, being different each other in terms of enzyme type, source and origin, and dosage.
This review, performed through a non-systematic search of the available literature, will provide an overview of the current knowledge of digestive enzyme supplementation in gastrointestinal disorders, discussion of the use of pancreatic enzymes, lactase (β-galactosidase) and conjugated bile acids, and also exploring the future perspective of digestive enzyme supplementation.
Currently, the animal-derived enzymes represent an established standard of care, however the growing study of plant-based and microbe-derived enzymes offers great promise in the advancement of digestive enzyme therapy.
New frontiers of enzyme replacement are being evaluated also in the treatment of diseases not specifically related to enzyme deficiency, whereas the combination of different enzymes might constitute an intriguing therapeutic option in the future.
Human diseases range from gene-associated to gene-non-associated disorders, including age-related diseases, neurodegenerative, neuromuscular, cardiovascular, diabetic diseases, neurocognitive ...disorders and cancer. Mitochondria participate to the cascades of pathogenic events leading to the onset and progression of these diseases independently of their association to mutations of genes encoding mitochondrial protein. Under physiological conditions, the mitochondrial ATP synthase provides the most energy of the cell via the oxidative phosphorylation. Alterations of oxidative phosphorylation mainly affect the tissues characterized by a high-energy metabolism, such as nervous, cardiac and skeletal muscle tissues. In this review, we focus on human diseases caused by altered expressions of ATP synthase genes of both mitochondrial and nuclear origin. Moreover, we describe the contribution of ATP synthase to the pathophysiological mechanisms of other human diseases such as cardiovascular, neurodegenerative diseases or neurocognitive disorders.
The permeability transition pore (PTP) is a Ca2+‐dependent mitochondrial channel whose opening causes a permeability increase in the inner membrane to ions and solutes. The most potent inhibitors are ...matrix protons, with channel block at pH 6.5. Inhibition is reversible, mediated by histidyl residue(s), and prevented by their carbethoxylation by diethylpyrocarbonate (DPC), but their assignment is unsolved. We show that PTP inhibition by H+ is mediated by the highly conserved histidyl residue (H112 in the human mature protein) of oligomycin sensitivity conferral protein (OSCP) subunit of mitochondrial F1FO (F)‐ATP synthase, which we also show to undergo carbethoxylation after reaction of mitochondria with DPC. Mitochondrial PTP‐dependent swelling cannot be inhibited by acidic pH in H112Q and H112Y OSCP mutants, and the corresponding megachannels (the electrophysiological counterpart of the PTP) are insensitive to inhibition by acidic pH in patch‐clamp recordings of mitoplasts. Cells harboring the H112Q and H112Y mutations are sensitized to anoxic cell death at acidic pH. These results demonstrate that PTP channel formation and its inhibition by H+ are mediated by the F‐ATP synthase.
Synopsis
The unique histidine of the OSCP subunit of F‐ATP synthase mediates inhibition of the mitochondrial permeability transition pore by acidic pH, providing evidence that the pore forms from F‐ATP synthase through a mechanism involving its peripheral stalk.
The mitochondrial permeability transition pore is inhibited at pH 6.5.
Pore inhibition by acidic pH is lost in H112Q and H112Y mutants of OSCP subunit of F‐ATP synthase.
The peripheral stalk of F‐ATP synthase takes part in pore formation and pore inhibition by H+ is mediated by H112 of OSCP.
The unique histidine of the OSCP subunit of F‐ATP synthase mediates inhibition of the mitochondrial permeability transition pore by acidic pH, providing evidence that the pore forms from F‐ATP synthase through a mechanism involving its peripheral stalk.
Mitochondria play a central role in heart energy metabolism and Ca
2+ homeostasis and are involved in the pathogenesis of many forms of heart disease. The body of knowledge on mitochondrial ...pathophysiology in living cells and organs is increasing, and so is the interest in mitochondria as potential targets for cardioprotection. This critical review will focus on the permeability transition pore (PTP) and its regulation by cyclophilin (CyP) D as effectors of endogenous protective mechanisms and as potential drug targets. The complexity of the regulatory interactions underlying control of mitochondrial function in vivo is beginning to emerge, and although apparently contradictory findings still exist we believe that the network of regulatory protein interactions involving the PTP and CyPs in physiology and pathology will increase our repertoire for therapeutic interventions in heart disease. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.
► The permeability transition pore (PTP) is an inner membrane mitochondrial channel. ► Cyclosporin (Cs) A inhibits the pore through Cyclophilin (CyP) D, a matrix protein. ► The PTP is a major target for cardioprotection through CyPD inhibition. ► CyPD regulates other mitochondrial functions in a CsA-sensitive manner. ► We focus on PTP regulation by CyPD as a drug target for cardioprotection.
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