Mitochondrial calcium cycling in neuronal function and neurodegeneration.

Mitochondria are essential for proper cellular function through their critical roles in ATP synthesis, reactive oxygen species production, calcium (Ca2+) buffering, and apoptotic signaling. In neurons, Ca2+ buffering is particularly important as it helps to shape Ca2+ signals and to regulate numerous Ca2+-dependent functions including neuronal excitability, synaptic transmission, gene expression, and neuronal toxicity. Over the past decade, identification of the mitochondrial Ca2+ uniporter (MCU) and other molecular components of mitochondrial Ca2+ transport has provided insight into the roles that mitochondrial Ca2+ regulation plays in neuronal function in health and disease. In this review, we discuss the many roles of mitochondrial Ca2+ uptake and release mechanisms in normal neuronal function and highlight new insights into the Ca2+-dependent mechanisms that drive mitochondrial dysfunction in neurologic diseases including epilepsy, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We also consider how targeting Ca2+ uptake and release mechanisms could facilitate the development of novel therapeutic strategies for neurological diseases.

MCU (mitochondrial Ca2+ uniporter) makes the calcium go round.

Store-operated Ca2+ entry (SOCE) is a major mechanism controlling Ca2+ signaling and Ca2+-dependent functions and has been implicated in immunity, cancer, and organ development. SOCE-dependent cytosolic Ca2+ signals are affected by mitochondrial Ca2+ transport through several competing mechanisms. However, how these mechanisms interact in shaping Ca2+ dynamics and regulating Ca2+-dependent functions remains unclear. In a recent issue, Yoast et al. shed light on these questions by defining multiple roles of the mitochondrial Ca2+ uniporter in regulating SOCE, Ca2+ dynamics, transcription, and lymphocyte activation.

Electro-Optic Modulation Using Metal-Free Perovskites.

Electro-optic (EO) modulation is of interest to impart information onto an optical carrier. Inorganic crystals-most notably LiNbO3 and BaTiO3-exhibit EO modulation and good stability, but are difficult to integrate with silicon photonic technology. Solution-processed organic EO materials are readily integrated but suffer from thermal degradation at the temperatures required in operating conditions for accelerated reliability studies. Hybrid organic-inorganic metal halide perovskites have the potential to overcome these limitations; however, these have so far relied on heavy metals such as lead and cadmium. Here, we report linear EO modulation using metal-free perovskites, which maintain the crystalline features of the inorganic EO materials and incorporate the flexible functionality of organic EO chromophores. We find that, by introducing a deficiency of cations, we reduce the symmetry in the perovskite crystal and produce thereby an increased EO response. The best-engineered perovskites reported herein showcase an EO coefficient of 14 pm V-1 at a modulation frequency of 80 kHz, an order of magnitude higher than in the nondefective materials. We observe split peaks in the X-ray diffraction and neutron diffraction patterns of the defective sample, indicating that the crystalline structure has been distorted and the symmetry reduced. Density functional theory (DFT) studies link this decreased symmetry to NH4+ deficiencies. This demonstration of EO from metal-free perovskites highlights their potential in next-generation optical information transmission.

Distinct properties of Ca2+ efflux from brain, heart and liver mitochondria: The effects of Na+, Li+ and the mitochondrial Na+/Ca2+ exchange inhibitor CGP37157.

Mitochondrial Ca2+ transport is essential for regulating cell bioenergetics, Ca2+ signaling and cell death. Mitochondria accumulate Ca2+ via the mitochondrial Ca2+ uniporter (MCU), whereas Ca2+ is extruded by the mitochondrial Na+/Ca2+ (mtNCX) and H+/Ca2+ exchangers. The balance between these processes is essential for preventing toxic mitochondrial Ca2+ overload. Recent work demonstrated that MCU activity varies significantly among tissues, likely reflecting tissue-specific Ca2+ signaling and energy needs. It is less clear whether this diversity in MCU activity is matched by tissue-specific diversity in mitochondrial Ca2+ extrusion. Here we compared properties of mitochondrial Ca2+ extrusion in three tissues with prominent mitochondria function: brain, heart and liver. At the transcript level, expression of the Na+/Ca2+/Li+ exchanger (NCLX), which has been proposed to mediate mtNCX transport, was significantly greater in liver than in brain or heart. At the functional level, Na+ robustly activated Ca2+ efflux from brain and heart mitochondria, but not from liver mitochondria. The mtNCX inhibitor CGP37157 blocked Ca2+ efflux from brain and heart mitochondria but had no effect in liver mitochondria. Replacement of Na+ with Li+ to test the involvement of NCLX, resulted in a slowing of mitochondrial Ca2+ efflux by ∼70 %. Collectively, our findings suggest that mtNCX is responsible for Ca2+ extrusion from the mitochondria of the brain and heart, but plays only a small, if any, role in mitochondria of the liver. They also reveal that Li+ is significantly less effective than Na+ in driving mitochondrial Ca2+ efflux.

Bromine Incorporation and Suppressed Cation Rotation in Mixed-Halide Perovskites.

Engineering the composition of perovskite active layers has been critical in increasing the efficiency of perovskite solar cells (PSCs) to more than 25% in the latest reports. Partial substitutions of the monovalent cation and the halogen have been adopted in the highest-performing devices, but the precise role of bromine incorporation remains incompletely explained. Here we use quasi-elastic neutron scattering (QENS) to study, as a function of the degree of bromine incorporation, the dynamics of organic cations in triple-cation lead mixed-halide perovskites. We find that the inclusion of bromine suppresses low-energy rotations of formamidinium (FA), and we find that inhibiting FA rotation correlates with a longer-lived carrier lifetime. When the fraction of bromine approaches 0.15 on the halogen site-a composition used extensively in the PSC literature-the fraction of actively rotating FA molecules is minimized: indeed, the fraction of rotating FA is suppressed by more than 25% compared to the bromine-free perovskite.

FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake.

Fibroblast growth factor 21 (FGF21) is an endocrine hormone produced by the liver that regulates nutrient and metabolic homeostasis. FGF21 production is increased in response to macronutrient imbalance and signals to the brain to suppress sugar intake and sweet-taste preference. However, the central targets mediating these effects have been unclear. Here, we identify FGF21 target cells in the hypothalamus and reveal that FGF21 signaling to glutamatergic neurons is both necessary and sufficient to mediate FGF21-induced sugar suppression and sweet-taste preference. Moreover, we show that FGF21 acts directly in the ventromedial hypothalamus (VMH) to specifically regulate sucrose intake, but not non-nutritive sweet-taste preference, body weight, or energy expenditure. Finally, our data demonstrate that FGF21 affects neuronal activity by increasing activation and excitability of neurons in the VMH. Thus, FGF21 signaling to glutamatergic neurons in the VMH is an important component of the neurocircuitry that functions to regulate sucrose intake.

Heterogeneous Supersaturation in Mixed Perovskites.

Thin-film solar cells based on hybrid lead halide perovskites have achieved certified power conversion efficiencies exceeding 24%, approaching those of crystalline silicon. This motivates deeper studies of the mechanisms that determine their performance. Twin defect sites have been proposed as a source of traps in perovskites, yet their origin and influence on photovoltaic performance remain unclear. It is found that twin defects-observed herein via both transmission electron microscopy and X-ray diffraction-are correlated with the amount of antisolvent added to the perovskite and that twin defects in the highest-performing perovskite photovoltaics are suppressed. Heterogeneous supersaturation nucleation is discussed as a contributor to efficient perovskite-based optoelectronic devices.

Directional Light Emission from Layered Metal Halide Perovskite Crystals.

Metal halide perovskites are being increasingly explored for use in light-emitting diodes (LEDs), with achievements in efficiency and brightness charted across the spectrum. One path to further boosting the fraction of useful photons generated by injected electrical charges will be to tailor the emission patterns of devices. Here we investigate directional emission from layered metal halide perovskites. We quantify the proportion of in-plane versus out-of-plane transition dipole components for a suite of layered perovskites. We find that certain perovskite single crystals have highly anisotropic emissions and up to 90% of their transition dipole in-plane. For thin films, emission anisotropy increases as the nominal layer thickness decreases and is generally greater with butylammonium cations than with phenethylammonium cations. Numerical simulations reveal that anisotropic emission from layered perovskites in thin-film LEDs may lead to external quantum efficiencies of 45%, an absolute gain of 13% over equivalent films with isotropic emitters.

Deletion of a Neuronal Drp1 Activator Protects against Cerebral Ischemia.

Mitochondrial fission catalyzed by dynamin-related protein 1 (Drp1) is necessary for mitochondrial biogenesis and maintenance of healthy mitochondria. However, excessive fission has been associated with multiple neurodegenerative disorders, and we recently reported that mice with smaller mitochondria are sensitized to ischemic stroke injury. Although pharmacological Drp1 inhibition has been put forward as neuroprotective, the specificity and mechanism of the inhibitor used is controversial. Here, we provide genetic evidence that Drp1 inhibition is neuroprotective. Drp1 is activated by dephosphorylation of an inhibitory phosphorylation site, Ser637. We identify Bß2, a mitochondria-localized protein phosphatase 2A (PP2A) regulatory subunit, as a neuron-specific Drp1 activator in vivo Bß2 KO mice of both sexes display elongated mitochondria in neurons and are protected from cerebral ischemic injury. Functionally, deletion of Bß2 and maintained Drp1 Ser637 phosphorylation improved mitochondrial respiratory capacity, Ca2+ homeostasis, and attenuated superoxide production in response to ischemia and excitotoxicity in vitro and ex vivo Last, deletion of Bß2 rescued excessive stroke damage associated with dephosphorylation of Drp1 S637 and mitochondrial fission. These results indicate that the state of mitochondrial connectivity and PP2A/Bß2-mediated dephosphorylation of Drp1 play a critical role in determining the severity of cerebral ischemic injury. Therefore, Bß2 may represent a target for prophylactic neuroprotective therapy in populations at high risk of stroke.SIGNIFICANCE STATEMENT With recent advances in clinical practice including mechanical thrombectomy up to 24 h after the ischemic event, there is resurgent interest in neuroprotective stroke therapies. In this study, we demonstrate reduced stroke damage in the brain of mice lacking the Bß2 regulatory subunit of protein phosphatase 2A, which we have shown previously acts as a positive regulator of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). Importantly, we provide evidence that deletion of Bß2 can rescue excessive ischemic damage in mice lacking the mitochondrial PKA scaffold AKAP1, apparently via opposing effects on Drp1 S637 phosphorylation. These results highlight reversible phosphorylation in bidirectional regulation of Drp1 activity and identify Bß2 as a potential pharmacological target to protect the brain from stroke injury.

Combining Efficiency and Stability in Mixed Tin-Lead Perovskite Solar Cells by Capping Grains with an Ultrathin 2D Layer.

The development of narrow-bandgap (Eg ≈ 1.2 eV) mixed tin-lead (Sn-Pb) halide perovskites enables all-perovskite tandem solar cells. Whereas pure-lead halide perovskite solar cells (PSCs) have advanced simultaneously in efficiency and stability, achieving this crucial combination remains a challenge in Sn-Pb PSCs. Here, Sn-Pb perovskite grains are anchored with ultrathin layered perovskites to overcome the efficiency-stability tradeoff. Defect passivation is achieved both on the perovskite film surface and at grain boundaries, an approach implemented by directly introducing phenethylammonium ligands in the antisolvent. This improves device operational stability and also avoids the excess formation of layered perovskites that would otherwise hinder charge transport. Sn-Pb PSCs with fill factors of 79% and a certified power conversion efficiency (PCE) of 18.95% are reported-among the highest for Sn-Pb PSCs. Using this approach, a 200-fold enhancement in device operating lifetime is achieved relative to the nonpassivated Sn-Pb PSCs under full AM1.5G illumination, and a 200 h diurnal operating time without efficiency drop is achieved under filtered AM1.5G illumination.

Multi-cation perovskites prevent carrier reflection from grain surfaces.

The composition of perovskite has been optimized combinatorially such that it often contains six components (AxByC1-x-yPbXzY3-z) in state-of-art perovskite solar cells. Questions remain regarding the precise role of each component, and the lack of a mechanistic explanation limits the practical exploration of the large and growing chemical space. Here, aided by transient photoluminescence microscopy, we find that, in perovskite single crystals, carrier diffusivity is in fact independent of composition. In polycrystalline thin films, the different compositions play a crucial role in carrier diffusion. We report that methylammonium (MA)-based films show a high carrier diffusivity of 0.047 cm2 s-1, while MA-free mixed caesium-formamidinium (CsFA) films exhibit an order of magnitude lower diffusivity. Elemental composition studies show that CsFA grains display a graded composition. This curtails electron diffusion in these films, as seen in both vertical carrier transport and surface potential studies. Incorporation of MA leads to a uniform grain core-to-edge composition, giving rise to a diffusivity of 0.034 cm2 s-1 in CsMAFA films. A model that invokes competing crystallization processes allows us to account for this finding, and suggests further strategies to achieve homogeneous crystallization for the benefit of perovskite optoelectronics.

Cascade surface modification of colloidal quantum dot inks enables efficient bulk homojunction photovoltaics.

Control over carrier type and doping levels in semiconductor materials is key for optoelectronic applications. In colloidal quantum dots (CQDs), these properties can be tuned by surface chemistry modification, but this has so far been accomplished at the expense of reduced surface passivation and compromised colloidal solubility; this has precluded the realization of advanced architectures such as CQD bulk homojunction solids. Here we introduce a cascade surface modification scheme that overcomes these limitations. This strategy provides control over doping and solubility and enables n-type and p-type CQD inks that are fully miscible in the same solvent with complete surface passivation. This enables the realization of homogeneous CQD bulk homojunction films that exhibit a 1.5 times increase in carrier diffusion length compared with the previous best CQD films. As a result, we demonstrate the highest power conversion efficiency (13.3%) reported among CQD solar cells.

Edge stabilization in reduced-dimensional perovskites.

Reduced-dimensional perovskites are attractive light-emitting materials due to their efficient luminescence, color purity, tunable bandgap, and structural diversity. A major limitation in perovskite light-emitting diodes is their limited operational stability. Here we demonstrate that rapid photodegradation arises from edge-initiated photooxidation, wherein oxidative attack is powered by photogenerated and electrically-injected carriers that diffuse to the nanoplatelet edges and produce superoxide. We report an edge-stabilization strategy wherein phosphine oxides passivate unsaturated lead sites during perovskite crystallization. With this approach, we synthesize reduced-dimensional perovskites that exhibit 97 ± 3% photoluminescence quantum yields and stabilities that exceed 300 h upon continuous illumination in an air ambient. We achieve green-emitting devices with a peak external quantum efficiency (EQE) of 14% at 1000 cd m-2; their maximum luminance is 4.5 × 104 cd m-2 (corresponding to an EQE of 5%); and, at 4000 cd m-2, they achieve an operational half-lifetime of 3.5 h.

Transition Dipole Moments of n = 1, 2, and 3 Perovskite Quantum Wells from the Optical Stark Effect and Many-Body Perturbation Theory.

Metal halide perovskite quantum wells (PQWs) are quantum and dielectrically confined materials exhibiting strongly bound excitons. The exciton transition dipole moment dictates absorption strength and influences interwell coupling in dipole-mediated energy transfer, a process that influences the performance of PQW optoelectronic devices. Here we use transient reflectance spectroscopy with circularly polarized laser pulses to investigate the optical Stark effect in dimensionally pure single crystals of n = 1, 2, and 3 Ruddlesden-Popper PQWs. From these measurements, we extract in-plane transition dipole moments of 11.1 (±0.4), 9.6 (±0.6) and 13.0 (±0.8) D for n = 1, 2 and 3, respectively. We corroborate our experimental results with density functional and many-body perturbation theory calculations, finding that the nature of band edge orbitals and exciton wave function delocalization depends on the PQW "odd-even" symmetry. This accounts for the nonmonotonic relationship between transition dipole moment and PQW dimensionality in the n = 1-3 range.

Lattice anchoring stabilizes solution-processed semiconductors.

The stability of solution-processed semiconductors remains an important area for improvement on their path to wider deployment. Inorganic caesium lead halide perovskites have a bandgap well suited to tandem solar cells1 but suffer from an undesired phase transition near room temperature2. Colloidal quantum dots (CQDs) are structurally robust materials prized for their size-tunable bandgap3; however, they also require further advances in stability because they are prone to aggregation and surface oxidization at high temperatures as a consequence of incomplete surface passivation4,5. Here we report 'lattice-anchored' hybrid materials that combine caesium lead halide perovskites with lead chalcogenide CQDs, in which lattice matching between the two materials contributes to a stability exceeding that of the constituents. We find that CQDs keep the perovskite in its desired cubic phase, suppressing the transition to the undesired lattice-mismatched phases. The stability of the CQD-anchored perovskite in air is enhanced by an order of magnitude compared with pristine perovskite, and the material remains stable for more than six months at ambient conditions (25 degrees Celsius and about 30 per cent humidity) and more than five hours at 200 degrees Celsius. The perovskite prevents oxidation of the CQD surfaces and reduces the agglomeration of the nanoparticles at 100 degrees Celsius by a factor of five compared with CQD controls. The matrix-protected CQDs show a photoluminescence quantum efficiency of 30 per cent for a CQD solid emitting at infrared wavelengths. The lattice-anchored CQD:perovskite solid exhibits a doubling in charge carrier mobility as a result of a reduced energy barrier for carrier hopping compared with the pure CQD solid. These benefits have potential uses in solution-processed optoelectronic devices.

Anchored Ligands Facilitate Efficient B-Site Doping in Metal Halide Perovskites.

Metal halide perovskites exhibit outstanding optoelectronic properties: superior charge carrier mobilities, low densities of deep trap states, high photoluminescence quantum yield, and wide color tunability. The introduction of dopant ions provides pathways to manipulate the electronic and chemical features of perovskites. In metal halide perovskites ABX3, where A is a monovalent cation (e.g., methylammonium (MA+), Cs+), B is the divalent metal ion(s) (e.g., Pb2+, Sn2+), and X is the halide group (e.g., Cl-, Br-, or I-), the isovalent exchange of A- and X-site ions has been widely accomplished; in contrast, strategies to exchange B-site cations are underexamined. The activation energies for vacancy-mediated diffusion of B-site cations are much higher than those for A- and X-sites, leading to slow doping processes and low doping ratios. Herein we demonstrate a new method that exchanges B-site cations in perovskites. We design a series of metal carboxylate solutions that anchor on the perovskite surface, allowing fast and efficient doping of B-sites with both homovalent and heterovalent cations (e.g., Sn2+, Zn2+, Bi3+) at room temperature. The doping process in the reduced-dimensional perovskites is complete within 1 min, whereas a similar reaction only leads to the surface attachment of dopant ions in three-dimensional structures. We offer a model based on ammonium extraction and surface ion-pair substitution.

Contactless measurements of photocarrier transport properties in perovskite single crystals.

The remarkable properties of metal halide perovskites arising from their impressive charge carrier diffusion lengths have led to rapid advances in solution-processed optoelectronics. Unfortunately, diffusion lengths reported in perovskite single crystals have ranged widely - from 3 µm to 3 mm - for ostensibly similar materials. Here we report a contactless method to measure the carrier mobility and further extract the diffusion length: our approach avoids both the effects of contact resistance and those of high electric field. We vary the density of quenchers - epitaxially included within perovskite single crystals - and report the dependence of excited state lifetime in the perovskite on inter-quencher spacing. Our results are repeatable and self-consistent (i.e. they agree on diffusion length for many different quencher concentrations) to within ± 6%. Using this method, we obtain a diffusion length in metal-halide perovskites of 2.6 µm ± 0.1 µm.

A Facet-Specific Quantum Dot Passivation Strategy for Colloid Management and Efficient Infrared Photovoltaics.

Colloidal nanocrystals combine size- and facet-dependent properties with solution processing. They offer thus a compelling suite of materials for technological applications. Their size- and facet-tunable features are studied in synthesis; however, to exploit their features in optoelectronic devices, it will be essential to translate control over size and facets from the colloid all the way to the film. Larger-diameter colloidal quantum dots (CQDs) offer the attractive possibility of harvesting infrared (IR) solar energy beyond absorption of silicon photovoltaics. These CQDs exhibit facets (nonpolar (100)) undisplayed in small-diameter CQDs; and the materials chemistry of smaller nanocrystals fails consequently to translate to materials for the short-wavelength IR regime. A new colloidal management strategy targeting the passivation of both (100) and (111) facets is demonstrated using distinct choices of cations and anions. The approach leads to narrow-bandgap CQDs with impressive colloidal stability and photoluminescence quantum yield. Photophysical studies confirm a reduction both in Stokes shift (≈47 meV) and Urbach tail (≈29 meV). This approach provides a ≈50% increase in the power conversion efficiency of IR photovoltaics compared to controls, and a ≈70% external quantum efficiency at their excitonic peak.

Electro-Optic Modulation in Hybrid Metal Halide Perovskites.

Rapid and efficient conversion of electrical signals to optical signals is needed in telecommunications and data network interconnection. The linear electro-optic (EO) effect in noncentrosymmetric materials offers a pathway to such conversion. Conventional inorganic EO materials make on-chip integration challenging, while organic nonlinear molecules suffer from thermodynamic molecular disordering that decreases the EO coefficient of the material. It has been posited that hybrid metal halide perovskites could potentially combine the advantages of inorganic materials (stable crystal orientation) with those of organic materials (solution processing). Here, layered metal halide perovskites are reported and investigated for in-plane birefringence and linear electro-optic response. Phenylmethylammonium lead chloride (PMA2 PbCl4 ) crystals are grown that exhibit a noncentrosymmetric space group. Birefringence measurements and Raman spectroscopy confirm optical and structural anisotropy in the material. By applying an electric field on the crystal surface, the linear EO effect in PMA2 PbCl4 is reported and its EO coefficient is determined to be 1.40 pm V-1 . This is the first demonstration of this effect in hybrid metal halide perovskites, materials that feature both highly ordered crystalline structures and solution processability. The in-plane birefringence and electro-optic response reveal that layered perovskite crystals could be further explored for potential applications in polarizing optics and EO modulation.