1,721,106 research outputs found
GPR35, ally of the anti-ischemic ATPIF1-ATP synthase interaction
Full text linkMitochondrial ATP synthase synthesizes ATP for cellular functions; however, under various conditions, including ischemia, it hydrolyzes ATP, primarily to re-energize the mitochondria. ATP synthase inhibitory factor 1 (ATPIF1) inhibits hydrolysis of ATP by ATP synthase. Wyant and colleagues recently demonstrated that G-protein-coupled receptor 35 (GPR35) is involved in this process. This finding provides an additional framework for the novel discovery of potential therapeutic molecules against ischemia/reperfusion (I/R) injury
What happens when the mitochondrial H+-translocating F1FO-ATP(hydrol)ase becomes a molecular target of calcium? The pore opens
Full text link: The F1FO-ATPase has Mg2+ cofactor as the natural divalent cation to support the bifunctional activity of ATP synthesis and hydrolysis. Different physio(patho)logical conditions permit the molecular interaction of Ca2+ with the enzyme and the modification of the biological role. Three distinct binding regions of Ca2+ have been localized on the enzyme complex: one in the F1 catalytic sites and the other two sites in the membrane-embedded domain FO. In all likelihood, Ca2+-activated enzyme most frequently works as an H+-translocating F1FO-ATP(hydrol)ase with a monofunctional activity that triggers the formation of mitochondrial permeability transition pore (mPTP) phenomenon. The protein(s) component of the mPTP is considered an arcane mystery. However, the F1FO-ATPase could reveal the molecular mechanism of pore opening when Ca2+ is bound to the enzyme. In this regard, the role of Ca2+-dependent function of the F1FO-ATPase in the formation of the mPTP is discussed
Proton leak through the UCPs and ANT carriers and beyond: A breath for the electron transport chain
Full text link: Mitochondria produce heat as a result of an ineffective H+ cycling of mitochondria respiration across the inner mitochondrial membrane (IMM). This event present in all mitochondria, known as proton leak, can decrease protonmotive force (Δp) and restore mitochondrial respiration by partially uncoupling the substrate oxidation from the ADP phosphorylation. During impaired conditions of ATP generation with F1FO-ATPase, the Δp increases and IMM is hyperpolarized. In this bioenergetic state, the respiratory complexes support H+ transport until the membrane potential stops the H+ pump activity. Consequently, the electron transfer is stalled and the reduced form of electron carriers of the respiratory chain can generate O2∙ ̅ triggering the cascade of ROS formation and oxidative stress. The physiological function to attenuate the production of O2∙ ̅ by Δp dissipation can be attributed to the proton leak supported by the translocases of IMM
The mitochondrial permeability transition and the connection between F1FO-ATPase and calcium
No full textNo abstract availabl
Bacterial and mammalian F1FO-ATPase: Structural similarities and divergences to exploit in the battle against Mycobacterium tuberculosis
No full text: The inner mitochondrial membrane, thylakoid membrane of chloroplasts and bacterial plasma membrane play a central role in energy transduction processes exploiting a ubiquitous membrane-bound enzyme complex known as F1FO-ATPase. The enzyme maintains the same function of ATP production between the species and a basic molecular mechanism of enzymatic catalysis during ATP synthesis/hydrolysis. However, small structural divergences distinguish prokaryotic ATP synthases, embedded in cell membranes, from eukaryotic ones localized in the inner mitochondrial membrane designating the bacterial enzyme as drug targets. In antimicrobial drug design, the membrane-embedded c-ring of the enzyme becomes the key protein of candidate compounds, such as diarylquinolines in tuberculosis, that inhibit the mycobacteria F1FO-ATPase without affecting mammalian homologs. The drug known as bedaquiline can target uniquely the structure of the mycobacterial c-ring. This specific interaction could address at the molecular level the therapy of infections sustained by antibiotic-resistant microorganisms
The mitochondrial permeability transition pore in cell death: A promising drug binding bioarchitecture
Full text linkBioenergetic failure often features programmed cell death involved in some severe pathologies. When the cell is fated to die, the inner mitochondrial membrane becomes permeable to ions and solutes, due to the formation and opening of a channel known as mitochondrial permeability transition pore (mPTP). Up to now, the still-elusive mPTP structure and mechanism prevented any attempt to identify/design drugs to rule its formation and limit cell death. Latest advances, which strongly suggest that the F1FO-ATPase can coincide with the mPTP, open new perspectives in therapy. Compounds targeting and inhibiting cyclophilin D, a known mPTP promoter, could be exploited to block mPTP formation. Moreover, if the mPTP-F1FO-ATPase connection will be consolidated, selected F1FO-ATPase inhibitors could represent novel therapeutic options to attenuate mPTP-related diseases by directly acting on mPTP molecular mechanism. This intriguing perspective, which raises new hopes to counteract mPTP-related diseases, stimulates further studies to clarify the mPTP architecture and mechanism
A Lethal Channel between the ATP Synthase Monomers
No full textThe molecular structure of the transmembrane domain of ATP synthases is responsible for the inner mitochondrial membrane bending. According to the hypothesized mechanism, ATP synthase dissociation from dimers to monomers, triggered by Ca2+binding to F1, allows the mitochondrial permeability transition pore formation at the interface between the detached monomers
New insight in a new entity: the mitochondrial permeability transition pore arises from the Ca2+-activated F1FO-ATPases
No full text[No abstract available
SARS-CoV-2 first contact: spike-ACE2 interactions in COVID-19
No full textSARS-CoV-2 is a new virus belonging to the Coronaviridae family responsible for the rapid COVID-19 spread around the world. The Cryo-EM structure of the trimeric spike (S) protein showing the exposed receptor-binding domains (RBDs) ready for interactions with the host-cell receptors as well as the docking of the spike RBD onto the ACE2 of host cells may arise as the main COVID-19 therapeutic molecular target
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