MICU1 Interacts with the D-Ring of the MCU Pore to Control Its Ca2+ Flux and Sensitivity to Ru360.

Proper control of the mitochondrial Ca2+ uniporter's pore (MCU) is required to allow Ca2+-dependent activation of oxidative metabolism and to avoid mitochondrial Ca2+ overload and cell death. The MCU's gatekeeping and cooperative activation is mediated by the Ca2+-sensing MICU1 protein, which has been proposed to form dimeric complexes anchored to the EMRE scaffold of MCU. We unexpectedly find that MICU1 suppresses inhibition of MCU by ruthenium red/Ru360, which bind to MCU's DIME motif, the selectivity filter. This led us to recognize in MICU1's sequence a putative DIME interacting domain (DID), which is required for both gatekeeping and cooperative activation of MCU and for cell survival. Thus, we propose that MICU1 has to interact with the D-ring formed by the DIME domains in MCU to control the uniporter.

The biological responses of osteoblasts on titanium: Effect of oxygen level and surface roughness.

BACKGROUND/PURPOSE: Due to the general application of in vitro test, cell culture is generally selected to evaluate the cytocompatibility of devices and materials. The choice of test condition should depend on the probable site and clinical application. The oxygen content of human body could be estimated around 5%∼12%, and the oxygen level of healing bone fracture range from 0.8%∼3.8%%. However, materials for bone implant are traditionally evaluated under laboratory normoxia condition (21% O2) in vitro. The aim was to study the effect of oxygen level on osteoblast upon high stiffness titanium with different roughness. METHODS: After sandblasted and acid-etched (SLA) process, we create titanium surfaces with four different roughness. The differentiation and proliferation of MC3T3-E1 osteoblast cultured on SLA-treated specimens were evaluated in designed chamber with oxygen level of 1%, 5%, 10%, 21%. RESULTS: By scanning electron microscopy, all samples had sub-micro pit inside the micro-holes upon SLA-treated Ti disk surface. The decrease of oxygen level from 21% to 5% promoted osteoblast growth of SLA-treated specimens, but 1% O2 delayed cell proliferation. The surface roughness of specimens influenced osteoblast cell differentiation. The differentiation and proliferation ability of the cells upon SLA-treated specimens is proportional to oxygen level. CONCLUSION: Our results demonstrated that 5% O2 will easily discriminate osteoblasts responses on different SLA-treated specimens. These results suggest that hypoxia (5% O2) environment is better model for biological evaluation of bone-related materials.

Molecular pathophysiology of human MICU1 deficiency.

AIMS: MICU1 encodes the gatekeeper of the mitochondrial Ca2+ uniporter, MICU1 and biallelic loss-of-function mutations cause a complex, neuromuscular disorder in children. Although the role of the protein is well understood, the precise molecular pathophysiology leading to this neuropaediatric phenotype has not been fully elucidated. Here we aimed to obtain novel insights into MICU1 pathophysiology. METHODS: Molecular genetic studies along with proteomic profiling, electron-, light- and Coherent anti-Stokes Raman scattering microscopy and immuno-based studies of protein abundances and Ca2+ transport studies were employed to examine the pathophysiology of MICU1 deficiency in humans. RESULTS: We describe two patients carrying MICU1 mutations, two nonsense (c.52C>T; p.(Arg18*) and c.553C>T; p.(Arg185*)) and an intragenic exon 2-deletion presenting with ataxia, developmental delay and early onset myopathy, clinodactyly, attention deficits, insomnia and impaired cognitive pain perception. Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles and altered lipid homeostasis. Comparative mitochondrial Ca2+ transport and proteomic studies on lymphoblastoid cells revealed that the [Ca2+ ] threshold and the cooperative activation of mitochondrial Ca2+ uptake were lost in MICU1-deficient cells and that 39 proteins were altered in abundance. Several of those proteins are linked to mitochondrial dysfunction and/or perturbed Ca2+ homeostasis, also impacting on regular cytoskeleton (affecting Spectrin) and Golgi architecture, as well as cellular survival mechanisms. CONCLUSIONS: Our findings (i) link dysregulation of mitochondrial Ca2+ uptake with muscle pathology (including perturbed lipid homeostasis and ER-Golgi morphology), (ii) support the concept of a functional interplay of ER-Golgi and mitochondria in lipid homeostasis and (iii) reveal the vulnerability of the cellular proteome as part of the MICU1-related pathophysiology.

Structure-Property Relationships of Inorganic-Organic Hybrid Semiconducting Se-Fe-Cu-CO Polymers.

A novel family of inorganic-organic-hybrid SeFe3(CO)9-dipyridyl two- and one-dimensional Cu polymers was synthesized via the three-component liquid-assisted grinding (LAG) of [Cu(MeCN)4]+, inorganic cluster [SeFe3(CO)9]2- (1), and rigid conjugated dipyridyls 4,4'-dipyridyl (dpy) and 1,2-bis(4-pyridyl)ethylene (bpee) or flexible conjugation-interrupted dipyridyls 1,2-bis(4-pyridyl)ethane (bpea) and 1,3-bis(4-pyridyl)propane (bpp). They included a cluster-linked 2D polymer, [(µ4-Se)Fe3(CO)9Cu2(MeCN)(dpy)1.5]n (1-dpy-2D), a cluster-pendant 1D chain, [(µ3-Se)Fe3(CO)9Cu2(dpy)3]n (1-dpy-1D), cluster-blocked 1D polymers, [(µ3-Se)Fe3(CO)9Cu2(L)]n (1-L-1D, L = bpee, bpea), and a cluster-linked 2D polymer, [(µ4-Se)Fe3(CO)9Cu2(bpp)2]n (1-bpp-2D). The reversible dimensionality transformations of these three types of polymers accompanied by the change in coordination modes of 1 were achieved by the LAG addition of 1/[Cu(MeCN)4]+ or dipyridyl ligands. These polymers were found to possess tunable low-energy gaps (1.49-1.72 eV) that increased in the order regarding their structural features: cluster-linked 1-dpy-2D and 1-bpp-2D, cluster-blocked 1-bpea-1D and 1-bpee-1D, and cluster-pendant 1-dpy-1D and [(µ3-Se)Fe3(CO)9Cu2(L)2.5]n (L = bpee, 1-bpee-2D; bpea, 1-bpea-2D), indicative of the importance of the participation of cluster 1. The measured electrical conductivities of 1-bpp-2D, 1-bpea-1D, and 1-dpy-1D were 3.13 × 10-7, 2.92 × 10-7, and 2.30 × 10-7 S·cm-1, respectively, which were parallel for the trend in their energy gaps, revealing semiconducting behaviors, supported by XPS, XANES, and DFT calculations. The surprising semiconductivity of the conjugation-interrupted bpp-linked 1-bpp-2D was mainly ascribed to electron transport via C-H···O(carbonyl) hydrogen bonds and aromatic C-H···π contacts within its closely packed 2D layers. Water-/light-stable polymers 1-bpp-2D, 1-bpea-2D, and 1-dpy-1D were also demonstrated to exhibit excellent pseudo-first-order photodegradation toward nitroaromatics and organic dyes, where cluster-linked polymer 1-bpp-2D performed the best, as predicted by its structural features and narrow energy gap.

Cardioprotection by the mitochondrial unfolded protein response requires ATF5.

The mitochondrial unfolded protein response (UPRmt) is a cytoprotective signaling pathway triggered by mitochondrial dysfunction. UPRmt activation upregulates chaperones, proteases, antioxidants, and glycolysis at the gene level to restore proteostasis and cell energetics. Activating transcription factor 5 (ATF5) is a proposed mediator of the mammalian UPRmt. Herein, we hypothesized pharmacological UPRmt activation may protect against cardiac ischemia-reperfusion (I/R) injury in an ATF5-dependent manner. Accordingly, in vivo administration of the UPRmt inducers oligomycin or doxycycline 6 h before ex vivo I/R injury (perfused heart) was cardioprotective in wild-type but not global Atf5-/- mice. Acute ex vivo UPRmt activation was not cardioprotective, and loss of ATF5 did not impact baseline I/R injury without UPRmt induction. In vivo UPRmt induction significantly upregulated many known UPRmt-linked genes (cardiac quantitative PCR and Western blot analysis), and RNA-Seq revealed an UPRmt-induced ATF5-dependent gene set, which may contribute to cardioprotection. This is the first in vivo proof of a role for ATF5 in the mammalian UPRmt and the first demonstration that UPRmt is a cardioprotective drug target.NEW & NOTEWORTHY Cardioprotection can be induced by drugs that activate the mitochondrial unfolded protein response (UPRmt). UPRmt protection is dependent on activating transcription factor 5 (ATF5). This is the first in vivo evidence for a role of ATF5 in the mammalian UPRmt.

Dysregulated Ca2+ signaling, fluid secretion, and mitochondrial function in a mouse model of early Sjögren's disease.

The molecular mechanisms leading to saliva secretion are largely established, but factors that underlie secretory hypofunction, specifically related to the autoimmune disease Sjögren's syndrome (SS) are not fully understood. A major conundrum is the lack of association between the severity of salivary gland immune cell infiltration and glandular hypofunction. SS-like disease was induced by treatment with DMXAA, a small molecule agonist of murine STING. We have previously shown that the extent of salivary secretion is correlated with the magnitude of intracellular Ca2+ signals (Takano et al., 2021). Contrary to our expectations, despite a significant reduction in fluid secretion, neural stimulation resulted in enhanced Ca2+ signals with altered spatiotemporal characteristics in vivo. Muscarinic stimulation resulted in reduced activation of the Ca2+-activated Cl- channel, TMEM16a, although there were no changes in channel abundance or absolute sensitivity to Ca2+. Super-resolution microscopy revealed a disruption in the colocalization of Inositol 1,4,5-trisphosphate receptor Ca2+ release channels with TMEM16a, and channel activation was reduced when intracellular Ca2+ buffering was increased. These data indicate altered local peripheral coupling between the channels. Appropriate Ca2+ signaling is also pivotal for mitochondrial morphology and bioenergetics. Disrupted mitochondrial morphology and reduced oxygen consumption rate were observed in DMXAA-treated animals. In summary, early in SS disease, dysregulated Ca2+ signals lead to decreased fluid secretion and disrupted mitochondrial function contributing to salivary gland hypofunction.

Health assessment of emerging persistent organic pollutants (POPs) in PM2.5 in northern and central Taiwan.

Over the last two decades, Taiwan has effectively diminished atmospheric concentrations of polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) through the adept utilization of advanced technologies and the implementation of air pollution control devices. Despite this success, there exists a dearth of data regarding the levels of other PM2.5-bound organic pollutants and their associated health risks. To address this gap, our study comprehensively investigates the spatial and seasonal variations, potential sources, and health risks of PCDD/Fs, Polychlorinated biphenyls (PCBs), and Polychlorinated naphthalene (PCNs) in Northern and Central Taiwan. Sampling collections were conducted at three specific locations, including six municipal waste incinerators in Northern Taiwan, as well as a traffic and an industrial site in Central Taiwan. As a result, the highest mean values of PM2.5 (20.3-39.6 µg/m3) were observed at traffic sites, followed by industrial sites (14.4-39.3 µg/m3), and the vicinity of the municipal waste incinerator (12.4-29.4 µg/m3). Additionally, PCDD/Fs and PCBs exhibited discernible seasonal fluctuations, displaying higher concentrations in winter (7.53-11.9 and 0.09-0.12 fg I-TEQWHO/m3) and spring (7.02-13.7 and 0.11-0.16 fg I-TEQWHO/m3) compared to summer and autumn. Conversely, PCNs displayed no significant seasonal variations, with peak values observed in winter (0.05-0.10 fg I-TEQWHO/m3) and spring (0.03-0.08 fg I-TEQWHO/m3). Utilizing a Positive Matrix Factorization (PMF) model, sintering plants emerged as the predominant contributors to PCDD/Fs, constituting 77.9% of emissions. Woodchip boilers (68.3%) and municipal waste incinerators (21.0%) were identified as primary contributors to PCBs, while municipal waste incinerators (64.6%) along with a secondary copper and a copper sludge smelter (22.1%) were the principal sources of PCNs. Moreover, the study specified that individuals aged 19-70 in Northern Taiwan and those under the age of 12 years in Central Taiwan were found to have a significantly higher cancer risk, with values ranging from 9.26 x 10-9-1.12 x 10-7 and from 2.50 x 10-8-2.08 x 10-7respectively.

Dysregulated Ca2+ signaling, fluid secretion, and mitochondrial function in a mouse model of early Sjögren's syndrome.

Saliva is essential for oral health. The molecular mechanisms leading to physiological fluid secretion are largely established, but factors that underlie secretory hypofunction, specifically related to the autoimmune disease Sjögren's syndrome (SS) are not fully understood. A major conundrum is the lack of association between the severity of inflammatory immune cell infiltration within the salivary glands and glandular hypofunction. In this study, we investigated in a mouse model system, mechanisms of glandular hypofunction caused by the activation of the stimulator of interferon genes (STING) pathway. Glandular hypofunction and SS-like disease were induced by treatment with 5,6-Dimethyl-9-oxo-9H-xanthene-4-acetic acid (DMXAA), a small molecule agonist of murine STING. Contrary to our expectations, despite a significant reduction in fluid secretion in DMXAA-treated mice, in vivo imaging demonstrated that neural stimulation resulted in greatly enhanced spatially averaged cytosolic Ca2+ levels. Notably, however, the spatiotemporal characteristics of the Ca2+ signals were altered to signals that propagated throughout the entire cytoplasm as opposed to largely apically confined Ca2+ rises observed without treatment. Despite the augmented Ca2+ signals, muscarinic stimulation resulted in reduced activation of TMEM16a, although there were no changes in channel abundance or absolute sensitivity to Ca2+. However, super-resolution microscopy revealed a disruption in the intimate colocalization of Inositol 1,4,5-trisphosphate receptor Ca2+ release channels in relation to TMEM16a. TMEM16a channel activation was also reduced when intracellular Ca2+ buffering was increased. These data are consistent with altered local coupling between the channels contributing to the reduced activation of TMEM16a. Appropriate Ca2+ signaling is also pivotal for mitochondrial morphology and bioenergetics and secretion is an energetically expensive process. Disrupted mitochondrial morphology, a depolarized mitochondrial membrane potential, and reduced oxygen consumption rate were observed in DMXAA-treated animals compared to control animals. We report that early in SS disease, dysregulated Ca2+ signals lead to decreased fluid secretion and disrupted mitochondrial function contributing to salivary gland hypofunction and likely the progression of SS disease.

Loss of STIM1 and STIM2 in salivary glands disrupts ANO1 function but does not induce Sjogren's disease.

Sjogren's disease (SjD) is an autoimmune disease characterized by xerostomia (dry mouth), lymphocytic infiltration into salivary glands and the presence of SSA and SSB autoantibodies. Xerostomia is caused by hypofunction of the salivary glands and has been involved in the development of SjD. Saliva production is regulated by parasympathetic input into the glands initiating intracellular Ca 2+ signals that activate the store operated Ca 2+ entry (SOCE) pathway eliciting sustained Ca 2+ influx. SOCE is mediated by the STIM1 and STIM2 proteins and the ORAI1 Ca 2+ channel. However, there are no studies on the effects of lack of STIM1/2 function in salivary acini in animal models and its impact on SjD. Here we report that male and female mice lacking Stim1 and Stim2 ( Stim1/2 K14Cre ) in salivary glands showed reduced intracellular Ca 2+ levels via SOCE in parotid acini and hyposalivate upon pilocarpine stimulation. Bulk RNASeq of the parotid glands of Stim1/2 K14Cre mice showed a decrease in the expression of Stim1/2 but no other Ca 2+ associated genes mediating saliva fluid secretion. SOCE was however functionally required for the activation of the Ca 2+ activated chloride channel ANO1. Despite hyposalivation, ageing Stim1/2 K14Cre mice showed no evidence of lymphocytic infiltration in the glands or elevated levels of SSA or SSB autoantibodies in the serum, which may be linked to the downregulation of the toll-like receptor 8 ( Tlr8 ). By contrast, salivary gland biopsies of SjD patients showed increased STIM1 and TLR8 expression, and induction of SOCE in a salivary gland cell line increased the expression of TLR8 . Our data demonstrate that SOCE is an important activator of ANO1 function and saliva fluid secretion in salivary glands. They also provide a novel link between SOCE and TLR8 signaling which may explain why loss of SOCE does not result in SjD.

Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling.

Maintenance of the mitochondrial inner membrane potential (ΔΨM) is critical for many aspects of mitochondrial function, including mitochondrial protein import and ion homeostasis. While ΔΨM loss and its consequences are well studied, little is known about the effects of increased ΔΨM. In this study, we used cells deleted of ATPIF1, a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of mitochondrial hyperpolarization. Our data show that chronic ΔΨM increase leads to nuclear DNA hypermethylation, regulating transcription of mitochondria, carbohydrate and lipid metabolism genes. Surprisingly, remodeling of phospholipids, but not metabolites or redox changes, mechanistically links the ΔΨM to the epigenome. These changes were also observed upon chemical exposures and reversed by decreasing the ΔΨM, highlighting them as hallmark adaptations to chronic mitochondrial hyperpolarization. Our results reveal the ΔΨM as the upstream signal conveying the mitochondrial status to the epigenome to regulate cellular biology, providing a new framework for how mitochondria can influence health outcomes in the absence of canonical dysfunction.

MICU1 controls the sensitivity of the mitochondrial Ca2+ uniporter to activators and inhibitors.

Mitochondrial Ca2+ homeostasis loses its control in many diseases and might provide therapeutic targets. Mitochondrial Ca2+ uptake is mediated by the uniporter channel (mtCU), formed by MCU and is regulated by the Ca2+-sensing gatekeeper, MICU1, which shows tissue-specific stoichiometry. An important gap in knowledge is the molecular mechanism of the mtCU activators and inhibitors. We report that all pharmacological activators of the mtCU (spermine, kaempferol, SB202190) act in a MICU1-dependent manner, likely by binding to MICU1 and preventing MICU1's gatekeeping activity. These agents also sensitized the mtCU to inhibition by Ru265 and enhanced the Mn2+-induced cytotoxicity as previously seen with MICU1 deletion. Thus, MCU gating by MICU1 is the target of mtCU agonists and is a barrier for inhibitors like RuRed/Ru360/Ru265. The varying MICU1:MCU ratios result in different outcomes for both mtCU agonists and antagonists in different tissues, which is relevant for both pre-clinical research and therapeutic efforts.

Altered composition of the mitochondrial Ca2+uniporter in the failing human heart.

Heart failure (HF) is a leading cause of hospitalization and mortality worldwide. Yet, there is still limited knowledge on the underlying molecular mechanisms, because human tissue for research is scarce, and data obtained in animal models is not directly applicable to humans. Thus, studies of human heart specimen are of particular relevance. Mitochondrial Ca2+ handling is an emerging topic in HF progression because its regulation is central to the energy supply of the heart contractions as well as to avoiding mitochondrial Ca2+ overload and the ensuing cell death induction. Notably, animal studies have already linked impaired mitochondrial Ca2+ transport to the initiation/progression of HF. Mitochondrial Ca2+ uptake is mediated by the Ca2+uniporter (mtCU) that consists of the MCU pore under tight control by the Ca2+-sensing MICU1 and MICU2. The MICU1/MCU protein ratio has been validated as a predictor of the mitochondrial Ca2+ uptake phenotype. We here determined for the first time the protein composition of the mtCU in the human heart. The two regulators MICU1 and MICU2, were elevated in the failing human heart versus non-failing controls, while the MCU density was unchanged. Furthermore, the MICU1/MCU ratio was significantly elevated in the failing human hearts, suggesting altered gating of the MCU by MICU1 and MICU2. Based on a small cohort of patients, the decrease in the cardiac contractile function (ejection fraction) seems to correlate with the increase in MICU1/MCU ratio. Our findings therefore indicate a possible role for adaptive/maladaptive changes in the mtCU composition in the initiation/progression of human HF in humans and point to a potential therapeutic target at the level of the MICU1-dependent regulation of the mtCU.

Highly localized intracellular Ca2+ signals promote optimal salivary gland fluid secretion.

Salivary fluid secretion involves an intricate choreography of membrane transporters to result in the trans-epithelial movement of NaCl and water into the acinus lumen. Current models are largely based on experimental observations in enzymatically isolated cells where the Ca2+ signal invariably propagates globally and thus appears ideally suited to activate spatially separated Cl and K channels, present on the apical and basolateral plasma membrane, respectively. We monitored Ca2+ signals and salivary secretion in live mice expressing GCamp6F, following stimulation of the nerves innervating the submandibular gland. Consistent with in vitro studies, Ca2+ signals were initiated in the apical endoplasmic reticulum. In marked contrast to in vitro data, highly localized trains of Ca2+ transients that failed to fully propagate from the apical region were observed. Following stimuli optimum for secretion, large apical-basal gradients were elicited. A new mathematical model, incorporating these data was constructed to probe how salivary secretion can be optimally stimulated by apical Ca2+ signals.

Vesicular transport mediates the uptake of cytoplasmic proteins into mitochondria in Drosophila melanogaster.

Mitochondrial aging, which results in mitochondrial dysfunction, is strongly linked to many age-related diseases. Aging is associated with mitochondrial enlargement and transport of cytosolic proteins into mitochondria. The underlying homeostatic mechanisms that regulate mitochondrial morphology and function, and their breakdown during aging, remain unclear. Here, we identify a mitochondrial protein trafficking pathway in Drosophila melanogaster involving the mitochondria-associated protein Dosmit. Dosmit induces mitochondrial enlargement and the formation of double-membraned vesicles containing cytosolic protein within mitochondria. The rate of vesicle formation increases with age. Vesicles originate from the outer mitochondrial membrane as observed by tracking Tom20 localization, and the process is mediated by the mitochondria-associated Rab32 protein. Dosmit expression level is closely linked to the rate of ubiquitinated protein aggregation, which are themselves associated with age-related diseases. The mitochondrial protein trafficking route mediated by Dosmit offers a promising target for future age-related mitochondrial disease therapies.

Dysregulation of Mitochondrial Ca2+ Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1.

Muscle function is regulated by Ca2+, which mediates excitation-contraction coupling, energy metabolism, adaptation to exercise, and sarcolemmal repair. Several of these actions rely on Ca2+ delivery to the mitochondrial matrix via the mitochondrial Ca2+ uniporter, the pore of which is formed by mitochondrial calcium uniporter (MCU). MCU's gatekeeping and cooperative activation are controlled by MICU1. Loss-of-protein mutation in MICU1 causes a neuromuscular disease. To determine the mechanisms underlying the muscle impairments, we used MICU1 patient cells and skeletal muscle-specific MICU1 knockout mice. Both these models show a lower threshold for MCU-mediated Ca2+ uptake. Lack of MICU1 is associated with impaired mitochondrial Ca2+ uptake during excitation-contraction, aerobic metabolism impairment, muscle weakness, fatigue, and myofiber damage during physical activity. MICU1 deficit compromises mitochondrial Ca2+ uptake during sarcolemmal injury, which causes ineffective repair of the damaged myofibers. Thus, dysregulation of mitochondrial Ca2+ uptake hampers myofiber contractile function, likely through energy metabolism and membrane repair.

Alcohol-Soluble Cross-Linked Poly( nBA) n- b-Poly(NVTri) m Block Copolymer and Its Applications in Organic Photovoltaic Cells for Improved Stability.

In this study, a series of alcohol-soluble cross-linked block copolymers (BCPs) consisting of poly( n-butyl acrylate) (poly( nBA)) and poly( N-vinyl-1,2,4-triazole) (poly(NVTri)) blocks with different individual functions and lengths are designed and developed. These presynthesized cross-linked BCPs (PBA n-Tri m) were, for the first time, revealed to exhibit many advantages in serving as the electron-extraction layer (EEL) for organic photovoltaics (OPVs). The cross-linked BCPs possessed intense ionic functionality, showing well capability to form effective interfacial dipoles at the indium tin oxide interface to facilitate the charge extraction at the corresponding interface. Furthermore, it also consisted a core-shell structure, wherein the polar poly(NVTri) core was well protected by the poly( nBA) shell to endow improved robustness against solvent erosion and thermal/photo inputs. Consequently, the PBA70-Tri30 device yielded a decent power conversion efficiency of 8.03% with a Voc of 0.83 V, much exceeding the performance of the control device without using any EEL. Moreover, this device showed superior thermal stability/photostability. More than 80% of its initial performance was retained after being heated at 60 °C for 1000 h or exposed under continuous illumination (1 sun) for 1000 h, greatly surpassing the lifetime of the control device and the reference device using a common poly[(9,9-bis(3'-( N, N-dimethylamino)propyl)-2,7-fluorene)-alt-2,7-(9,9-dioctylfluorene)] (PFN) EEL. The results revealed the merit of using cross-linked BCPs in improving the long-term stability of OPVs.

MICU1 Confers Protection from MCU-Dependent Manganese Toxicity.

The mitochondrial calcium uniporter is a highly selective ion channel composed of species- and tissue-specific subunits. However, the functional role of each component still remains unclear. Here, we establish a synthetic biology approach to dissect the interdependence between the pore-forming subunit MCU and the calcium-sensing regulator MICU1. Correlated evolutionary patterns across 247 eukaryotes indicate that their co-occurrence may have conferred a positive fitness advantage. We find that, while the heterologous reconstitution of MCU and EMRE in vivo in yeast enhances manganese stress, this is prevented by co-expression of MICU1. Accordingly, MICU1 deletion sensitizes human cells to manganese-dependent cell death by disinhibiting MCU-mediated manganese uptake. As a result, manganese overload increases oxidative stress, which can be effectively prevented by NAC treatment. Our study identifies a critical contribution of MICU1 to the uniporter selectivity, with important implications for patients with MICU1 deficiency, as well as neurological disorders arising upon chronic manganese exposure.