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Ions play fundamental roles in all living cells, and their gradients are often essential to fuel transport, regulate enzyme activities, and transduce energy within cells. Regulation of their homeostasis is essential for cell metabolism. Recent results indicate that modulation of ion fluxes might also represent a useful strategy to regulate one of the most important physiological processes taking place in chloroplasts, photosynthesis. Photosynthesis is highly regulated, due to its unique role as a cellular engine for growth in the light. Controlling the balance between ATP and NADPH synthesis is a critical task, and availability of these molecules can limit the overall photosynthetic yield. Photosynthetic organisms optimize photosynthesis in low light, where excitation energy limits CO₂ fixation, and minimize photo-oxidative damage in high light by dissipating excess photons. Despite extensive studies of these phenomena, the mechanism governing light utilization in plants is still poorly understood. In this review, we provide an update of the recently identified chloroplast-located ion channels and transporters whose function impacts photosynthetic efficiency in plants.

F-ATP synthase is a leading candidate as the mitochondrial permeability transition pore (PTP) but the mechanism(s) leading to channel formation remain undefined. Here, to shed light on the structural requirements for PTP formation, we test cells ablated for g, OSCP and b subunits, and ρ 0 cells lacking subunits a and A6L. Δg cells (that also lack subunit e) do not show PTP channel opening in intact cells or patch-clamped mitoplasts unless atractylate is added. Δb and ΔOSCP cells display currents insensitive to cyclosporin A but inhibited by bongkrekate, suggesting that the adenine nucleotide translocator (ANT) can contribute to channel formation in the absence of an assembled F-ATP synthase. Mitoplasts from ρ 0 mitochondria display PTP currents indistinguishable from their wild-type counterparts. In this work, we show that peripheral stalk subunits are essential to turn the F-ATP synthase into the PTP and that the ANT provides mitochondria with a distinct permeability pathway. The nature of the mitochondrial permeability transition pore (PTP) is still under debate. Here, through genetically modified F-ATP synthase, the authors show that PTP formation can be mediated by F-ATP synthase or by adenine nucleotide translocator, suggesting the existence of distinct but related permeability pathways.

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. The molecular identity of the mitochondrial megachannel (MMC)/permeability transition pore (PTP), a key effector of cell death, remains controversial. Here authors demonstrate that the membrane embedded bovine F-ATP synthase elicits Ca2 + -dependent currents matching those of the MMC/PTP.

Mitochondrial calcium uniporter (MCU) channel is responsible for Ruthenium Red‐sensitive mitochondrial calcium uptake. Here, we demonstrate MCU oligomerization by immunoprecipitation and Förster resonance energy transfer (FRET) and characterize a novel protein (MCUb) with two predicted transmembrane domains, 50% sequence similarity and a different expression profile from MCU. Based on computational modelling, MCUb includes critical amino‐acid substitutions in the pore region and indeed MCUb does not form a calcium‐permeable channel in planar lipid bilayers. In HeLa cells, MCUb is inserted into the oligomer and exerts a dominant‐negative effect, reducing the [Ca 2+ ] mt increases evoked by agonist stimulation. Accordingly, in vitro co‐expression of MCUb with MCU drastically reduces the probability of observing channel activity in planar lipid bilayer experiments. These data unveil the structural complexity of MCU and demonstrate a novel regulatory mechanism, based on the inclusion of dominant‐negative subunits in a multimeric channel, that underlies the fine control of the physiologically and pathologically relevant process of mitochondrial calcium homeostasis. The ubiquitous mitochondrial calcium uniporter (MCU) oligomerizes to form pores. MCU also oligomerizes with a new dominant‐negative isoform, MCUb, which blocks calcium uptake revealing a new mechanism of mitochondrial calcium homeostasis and thus aerobic metabolism and apoptosis.

Mitochondria provide chemical energy for endoergonic reactions in the form of ATP, and their activity must meet cellular energy requirements, but the mechanisms that link organelle performance to ATP levels are poorly understood. Here we confirm the existence of a protein complex localized in mitochondria that mediates ATP-dependent potassium currents (that is, mitoK ATP ). We show that—similar to their plasma membrane counterparts—mitoK ATP channels are composed of pore-forming and ATP-binding subunits, which we term MITOK and MITOSUR, respectively. In vitro reconstitution of MITOK together with MITOSUR recapitulates the main properties of mitoK ATP . Overexpression of MITOK triggers marked organelle swelling, whereas the genetic ablation of this subunit causes instability in the mitochondrial membrane potential, widening of the intracristal space and decreased oxidative phosphorylation. In a mouse model, the loss of MITOK suppresses the cardioprotection that is elicited by pharmacological preconditioning induced by diazoxide. Our results indicate that mitoK ATP channels respond to the cellular energetic status by regulating organelle volume and function, and thereby have a key role in mitochondrial physiology and potential effects on several pathological processes. The pore-forming and ATP-binding subunits of a mitochondrial protein complex that mediates ATP-dependent potassium currents are identified and characterized, revealing the role of this channel in mitochondrial physiology and pathologies.

The pathology of Parkinson’s disease (PD) is characterized by α-synuclein aggregation, microglia-mediated neuroinflammation, and dopaminergic neurodegeneration in the substantia nigra with collateral striatal dopamine signaling deficiency. Microglial NLRP3 inflammasome activation has been linked independently to each of these facets of PD pathology. The voltage-gated potassium channel Kv1.3, upregulated in microglia by α-synuclein and facilitating potassium efflux, has also been identified as a modulator of neuroinflammation and neurodegeneration in models of PD. Evidence increasingly suggests that microglial Kv1.3 is mechanistically coupled with NLRP3 inflammasome activation, which is contingent on potassium efflux. Potassium conductance also influences dopamine release from midbrain dopaminergic neurons. Dopamine, in turn, has been shown to inhibit NLRP3 inflammasome activation in microglia. In this review, we provide a literature framework for a hypothesis in which Kv1.3 activity-induced NLRP3 inflammasome activation, evoked by stimuli such as α-synuclein, could lead to microglia utilizing dopamine from adjacent dopaminergic neurons to counteract this process and fend off an activated state. If this is the case, a sufficient dopamine supply would ensure that microglia remain under control, but as dopamine is gradually siphoned from the neurons by microglial demand, NLRP3 inflammasome activation and Kv1.3 activity would progressively intensify to promote each of the three major facets of PD pathology: α-synuclein aggregation, microglia-mediated neuroinflammation, and dopaminergic neurodegeneration. Risk factors overlapping to varying degrees to render brain regions susceptible to such a mechanism would include a high density of microglia, an initially sufficient supply of dopamine, and poor insulation of the dopaminergic neurons by myelin.

In natural habitats, plants frequently experience rapid changes in the intensity of sunlight. To cope with these changes and maximize growth, plants adjust photosynthetic light utilization in electron transport and photoprotective mechanisms. This involves a proton motive force (PMF) across the thylakoid membrane, postulated to be affected by unknown anion (Cl − ) channels. Here we report that a bestrophin-like protein from Arabidopsis thaliana functions as a voltage-dependent Cl − channel in electrophysiological experiments. AtVCCN1 localizes to the thylakoid membrane, and fine-tunes PMF by anion influx into the lumen during illumination, adjusting electron transport and the photoprotective mechanisms. The activity of AtVCCN1 accelerates the activation of photoprotective mechanisms on sudden shifts to high light. Our results reveal that AtVCCN1, a member of a conserved anion channel family, acts as an early component in the rapid adjustment of photosynthesis in variable light environments. Plants have evolved to maximize energy capture while protecting their photosynthetic machinery in response to rapid variation in light conditions. Here, the authors describe a chloroplast voltage-dependent anion channel that contributes to photoprotection by fine-tuning the ion balance across the thylakoid membrane.

Calcium has long been known to regulate the metabolism of chloroplasts, concerning both light and carbon reactions of photosynthesis, as well as additional non photosynthesis-related processes. In addition to undergo Ca regulation, chloroplasts can also influence the overall Ca signaling pathways of the plant cell. Compelling evidence indicate that chloroplasts can generate specific stromal Ca signals and contribute to the fine tuning of cytoplasmic Ca signaling in response to different environmental stimuli. The recent set up of a toolkit of genetically encoded Ca indicators, targeted to different chloroplast subcompartments (envelope, stroma, thylakoids) has helped to unravel the participation of chloroplasts in intracellular Ca handling in resting conditions and during signal transduction. Intra-chloroplast Ca signals have been demonstrated to occur in response to specific environmental stimuli, suggesting a role for these plant-unique organelles in transducing Ca -mediated stress signals. In this mini-review we present current knowledge of stimulus-specific intra-chloroplast Ca transients, as well as recent advances in the identification and characterization of Ca -permeable channels/transporters localized at chloroplast membranes. In particular, the potential role played by cMCU, a chloroplast-localized member of the mitochondrial calcium uniporter (MCU) family, as component of plant environmental sensing is discussed in detail, taking into account some specific structural features of cMCU. In summary, the recent molecular identification of some players of chloroplast Ca signaling has opened new avenues in this rapidly developing field and will hopefully allow a deeper understanding of the role of chloroplasts in shaping physiological responses in plants.

Mitochondrial ion channels are emerging oncological targets, as modulation of these ion-transporting proteins may impact on mitochondrial membrane potential, efficiency of oxidative phosphorylation and reactive oxygen production. In turn, these factors affect the release of cytochrome c, which is the point of no return during mitochondrial apoptosis. Many of the currently used chemotherapeutics induce programmed cell death causing damage to DNA and subsequent activation of p53-dependent pathways that finally leads to cytochrome c release from the mitochondrial inter-membrane space. The view is emerging, as summarized in the present review, that ion channels located in this organelle may account in several cases for the resistance that cancer cells can develop against classical chemotherapeutics, by preventing drug-induced apoptosis. Thus, pharmacological modulation of these channel activities might be beneficial to fight chemo-resistance of different types of cancer cells.

Ca2+ acts as an important cellular second messenger in eukaryotes. In both plants and animals, a wide variety of environmental and developmental stimuli trigger Ca2+ transients of a specific signature that can modulate gene expression and metabolism. In animals, mitochondrial energy metabolism has long been considered a hotspot of Ca2+ regulation, with a range of pathophysiology linked to altered Ca2+ control. Recently, several molecular players involved in mitochondrial Ca2+ signalling have been identified, including those of the mitochondrial Ca2+ uniporter. Despite strong evidence for sophisticated Ca2+ regulation in plant mitochondria, the picture has remained much less clear. This is currently changing aided by live imaging and genetic approaches which allow dissection of subcellular Ca2+ dynamics and identification of the proteins involved. We provide an update on our current understanding in the regulation of mitochondrial Ca2+ and signalling by comparing work in plants and animals. The significance of mitochondrial Ca2+ control is discussed in the light of the specific metabolic and energetic needs of plant and animal cells.