Liquid-liquid phase separation promotes the formation of membraneless condensates that mediate diverse cellular functions, including autophagy of misfolded proteins. However, how phase separation ...participates in autophagy of dysfunctional mitochondria (mitophagy) remains obscure. We previously discovered that nuclear receptor Nur77 (also called TR3, NGFI-B, or NR4A1) translocates from the nucleus to mitochondria to mediate celastrol-induced mitophagy through interaction with p62/SQSTM1. Here, we show that the ubiquitinated mitochondrial Nur77 forms membraneless condensates capable of sequestrating damaged mitochondria by interacting with the UBA domain of p62/SQSTM1. However, tethering clustered mitochondria to the autophagy machinery requires an additional interaction mediated by the N-terminal intrinsically disordered region (IDR) of Nur77 and the N-terminal PB1 domain of p62/SQSTM1, which confers Nur77-p62/SQSTM1 condensates with the magnitude and liquidity. Our results demonstrate how composite multivalent interaction between Nur77 and p62/SQSTM1 coordinates to sequester damaged mitochondria and to connect targeted cargo mitochondria for autophagy, providing mechanistic insight into mitophagy.
Summary
Brassinosteroids (BRs) play a critical role in plant growth, development and stress response; however, genetic evidence for the BR‐mediated integrated regulation of plant growth still remains ...elusive in crop species. Here, we clarified the function of DWARF (DWF), the key BR biosynthetic gene in tomato, in the regulation of plant growth and architecture, phytohormone homeostasis and fruit development by comparing wild type, d^im, a weak allele mutant impaired in DWF, and DWF‐overexpressing plants in tomato. Results showed that increases in DWF transcripts and endogenous BR level resulted in improved germination, lateral root development, CO2 assimilation and eventually plant growth as characterized by slender and compact plant architecture. However, an increase in DWF transcript down‐regulated the accumulation of gibberellin, which was associated with decreases in leaf size and thickness. BRs positively regulated lateral bud outgrowth, which was associated with decreased transcript of Aux/IAA3, and the ethylene‐dependent petiole bending and fruit ripening. Notably, overexpression of DWF did not significantly alter fruit yield per plant; however, increases by 57.4% and 95.3% might be estimated in fruit yield per square metre in two transgenic lines due to their compact architecture. Significantly, BR level was positively related with the carotenoid accumulation in the fruits. Taken together, our results demonstrate that BRs are actively involved in the regulation of multiple developmental processes relating to agronomical important traits.
Lithium (Li) metal-based battery is among the most promising candidates for next-generation rechargeable high-energy-density batteries. Carbon materials are strongly considered as the host of Li ...metal to relieve the powdery/dendritic Li formation and large volume change during repeated cycles. Herein, we describe the formation of a thin lithiophilic LiC
layer between carbon fibers (CFs) and metallic Li in Li/CF composite anode obtained through a one-step rolling method. An electron deviation from Li to carbon elevates the negativity of carbon atoms after Li intercalation as LiC
, which renders stronger binding between carbon framework and Li ions. The Li/CF | Li/CF batteries can operate for more than 90 h with a small polarization voltage of 120 mV at 50% discharge depth. The Li/CF | sulfur pouch cell exhibits a high discharge capacity of 3.25 mAh cm
and a large capacity retention rate of 98% after 100 cycles at 0.1 C. It is demonstrated that the as-obtained Li/CF composite anode with lithiophilic LiC
layers can effectively alleviate volume expansion and hinder dendritic and powdery morphology of Li deposits. This work sheds fresh light on the role of interfacial layers between host structure and Li metal in composite anode for long-lifespan working batteries.
B(C6F5)3 has been found to be an effective catalyst for reduction of pyridines and other electron‐deficient N‐heteroarenes with hydrosilanes (or hydroboranes) and amines as the reducing reagents. The ...success of this development hinges upon the realization of a cascade process of dearomative hydrosilylation (or hydroboration) and transfer hydrogenation. The broad functional‐group tolerance (e.g. ketone, ester, unactivated olefins, nitro, nitrile, heterocycles, etc.) implies high practical utility.
Reduction cascade: An operationally simple B(C6F5)3‐catalyzed pyridine reduction method has been developed. The reaction occurs by a cascade process of dearomative hydrosilylation (or hydroboration) and transfer hydrogenation. The reduction features very broad functional‐group tolerance.
Molecular-based ferroic phase-transition materials have attracted increasing attention in the past decades due to their promising potential as sensors, switches, and memory. One of the long-term ...challenges in the development of molecular-based ferroic materials is determining how to promote the ferroic phase-transition temperature (
T
c
). Herein, we present two new hexagonal molecular perovskites, (nortropinonium)CdCl
3
(
1
) and (nortropinium)CdCl
3
(
2
), to demonstrate a simple design principle for obtaining ultrahigh-
T
c
ferroelastic phase transitions. They consist of same host inorganic chains but subtly different guest organic cations featuring a rigid carbonyl and a flexible hydroxyl group in
1
and
2
, respectively. With stronger hydrogen bonds involving the carbonyl but a relatively lower decomposition temperature (
T
d
, 480 K),
1
does not exhibit a crystalline phase transition before its decomposition. The hydroxyl group subtly changes the balance of intermolecular interactions in
2
via
reducing the attractive hydrogen bonds but increasing the repulsive interactions between adjacent organic cations, which finally endows
2
with an enhanced thermal stability (
T
d
= 570 K) and three structural phase transitions, including two ferroelastic phase transitions at ultrahigh
T
c
values of 463 K and 495 K, respectively. This finding provides important clues to judiciously tuning the intermolecular interactions in hybrid crystals for developing high-
T
c
ferroic materials.
Two new hexagonal molecular perovskites with the same inorganic chain but subtly different organic cations exhibit distinct phase-transition behaviours owing to the different intermolecular interactions.
0.94(Na0.5Bi0.5+x)TiO3–0.06BaTiO3 (x = −0.04, 0, 0.02; named NB0.46T‐6BT, NB0.50T‐6BT, NB0.52T‐6BT, respectively) lead‐free piezoelectric ceramics were prepared via the solid‐state reaction method. ...Effects of Bi3+ nonstoichiometry on microstructure, dielectric, ferroelectric, and piezoelectric properties were studied. All ceramics show typical X‐ray diffraction peaks of ABO3 perovskite structure. The lattice parameters increase with the increase in the Bi3+ content. The electron probe microanalysis demonstrates that the excess Bi2O3 in the starting composition can compensate the Bi2O3 loss induced during sample processing. The size and shape of grains are closely related to the Bi3+ content. For the unpoled NB0.50T‐6BT and NB0.52T‐6BT, there are two dielectric anomalies in the dielectric constant–temperature curves. The unpoled NB0.46T‐6BT shows one dielectric anomaly accompanied by high dielectric constant and dielectric loss at low frequencies. After poling, a new dielectric anomaly appears around depolarization temperature (Td) for all ceramics and the Td values increase with the Bi3+ amount decreasing from excess to deficiency. The diffuse phase transition character was studied via the Curie–Weiss law and modified Curie–Weiss law. The activation energy values obtained via the impedance analysis are 0.69, 1.05, and 1.16 eV for NB0.46T‐6BT, NB0.50T‐6BT and NB0.52T‐6BT, respectively, implying the change in oxygen vacancy concentration in the ceramics. The piezoelectric constant, polarization, and coercive field of the ceramics change with the variation in the Bi3+ content. The Rayleigh analysis suggests that the change in electrical properties of the ceramics with the variation in the Bi3+ amount is related to the effect of oxygen vacancies.
Background and Purpose
Renal fibrosis is the final common outcome in most forms of chronic kidney disease (CKD). However, the underlying causal mechanisms remain obscure. The present study examined ...whether transmembrane member 16A (TMEM16A), a Ca2+‐activated chloride channel, contributes to the progression of renal fibrosis.
Experimental Approach
Masson staining, western blot and immunohistochemistry were used to measure renal fibrosis and related proteins expression. MQAE was used to evaluate the intracellular Cl− concentration.
Key Results
TMEM16A expression was significantly up‐regulated in fibrotic kidneys of unilateral ureteral obstruction (UUO) and high‐fat diet murine models and in renal samples of IgA nephropathy patients. In vivo knockdown of TMEM16A with adenovirus harbouring TMEM16A‐shRNA or inhibition of TMEM16A channel activity with inhibitors CaCCinh‐A01 or T16Ainh‐A01 effectively prevented UUO‐induced renal fibrosis and decreased protein expression of fibronectin, α‐SMA and collagen in the obstructed kidneys. In cultured HK2 cells, knockdown or inhibition of TMEM16A suppressed TGF‐β1‐induced epithelial–mesenchymal transition, reduced snail1 expression and phosphorylation of Smad2/3 and ERK1/2, whereas overexpression of TMEM16A showed the opposite effects. TGF‐β1 increased Cl−i in HK2 cells, which was inhibited by knockdown or inhibition of TMEM16A. Reducing Cl−i significantly blunted TGF‐β1‐induced Smad2/3 phosphorylation and profibrotic factors expression. The profibrotic effects of TGF‐β1 were also reduced by inhibition of serum‐ and glucocorticoid‐inducible protein kinase 1 (SGK1). SGK1 was also suppressed by reducing Cl−i.
Conclusion and Implications
Blockade of TMEM16A prevented the progression of kidney fibrosis, likely by suppressing Cl−i/SGK1/TGF‐β1 signalling pathway. TMEM16A may be a potential new therapeutic target against renal fibrosis.
BACKGROUND—Pathological cardiac hypertrophy induced by stresses such as aging and neurohumoral activation is an independent risk factor for heart failure and is considered a target for the treatment ...of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the roles of SIRT2 in aging-related and angiotensin II (Ang II)-induced pathological cardiac hypertrophy.
METHODS—Male C57BL/6J wild-type (WT) and Sirt2 knockout (Sirt2-KO) mice were subjected to the investigation of aging-related cardiac hypertrophy. Cardiac hypertrophy was also induced by Ang II (1.3 mg/kg/day for four weeks) in male C57BL/6J Sirt2-KO mice, cardiac-specific SIRT2 transgenic (SIRT2-Tg) mice and their respective littermates (8~12-week-old). Metformin (200 mg/kg/day) was used to treat WT and Sirt2-KO mice that were infused with Ang II. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice.
RESULTS—SIRT2 protein expression levels were down-regulated in hypertrophic hearts from mice. Sirt2-KO markedly exaggerated cardiac hypertrophy and fibrosis as well as decreases in cardiac ejection fraction and fractional shortening in aged (24-month-old) mice and Ang II-infused mice. Conversely, cardiac-specific SIRT2 overexpression protected the hearts against Ang II-induced cardiac hypertrophy and fibrosis and rescued cardiac function. Mechanistically, SIRT2 maintained the activity of AMP-activated protein kinase (AMPK) in aged and Ang II-induced hypertrophic hearts in vivo as well as in cardiomyocytes in vitro. We identified the liver kinase B1 (LKB1), the major upstream kinase of AMPK, as the direct target of SIRT2. SIRT2 bound to LKB1 and deacetylated it at lysine 48, which promoted the phosphorylation of LKB1 and the subsequent activation of LKB1-AMPK signaling. Remarkably, the loss of SIRT2 blunted the response of AMPK to metformin treatment in mice infused with Ang II and repressed the metformin-mediated reduction of cardiac hypertrophy and protection of cardiac function.
CONCLUSIONS—SIRT2 promotes AMPK activation by deacetylating the kinase LKB1. Loss of SIRT2 reduces AMPK activation, promotes aging-related and Ang II-induced cardiac hypertrophy and blunts metformin-mediated cardioprotective effects. These findings indicate that SIRT2 will be a potential target for therapeutic interventions in aging and stress-induced cardiac hypertrophy.
Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed in microglia in the brain. A soluble form of TREM2 (sTREM2) derived from proteolytic cleavage of the ...cell surface receptor is increased in the preclinical stages of AD and positively correlates with the amounts of total and phosphorylated tau in the cerebrospinal fluid. However, the physiological and pathological functions of sTREM2 remain unknown. Here, we show that sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-κB. Variants of sTREM2 carrying AD risk-associated mutations were less potent in both suppressing apoptosis and triggering inflammatory responses. Importantly, sTREM2 delivered to the hippocampi of both wild-type and
-knockout mice elevated the expression of inflammatory cytokines and induced morphological changes of microglia. Collectively, these data indicate that sTREM2 triggers microglial activation inducing inflammatory responses and promoting survival. This study has implications for the pathogenesis of AD and provides insights into targeting sTREM2 pathway for AD therapy.
Ferroelectric materials have a variety of technological applications, as transducers, capacitors, sensors, etc. Great interest in molecular ferroelectrics has emerged because of their structural ...flexibility, tunability, and homochirality. However, the discoveries of molecular ferroelectrics are not abundant. The lack of chemical design is the main challenge in realizing new molecular ferroelectrics. Consequently, chemical design approaches, including the ideas of introducing quasi-spherical theory, homochirality, and H/F substitution, have been developed recently. Through these advanced methodologies, a wide range of ferroelectrics were successfully synthesized, changing the blind search into a targeted chemical design. In this Perspective, we aim to provide insight into the fundamental chemistry and physics of molecular ferroelectrics and propose the concept of “ferroelectrochemistry”, concerned with the targeted design and performance optimization of molecular ferroelectrics from the chemical point of view. We start with the basic theories used in the modification of chemical structures for new molecular ferroelectrics, such as the quasi-spherical theory. After that, we focus on the fundamentals of homochirality from the perspective of chemistry and advantages of introducing a homochiral molecule within the scope of ferroelectrics. Further, we explore another design strategy, H/F substitution, as an analogue of the H/D isotope effect. The introduction of a F atom usually does not change the polar point group but may induce a minor structural disruption that enhances physical properties such as Curie temperature and spontaneous polarization. We hope our comprehensive studies on the targeted design and performance optimization strategies for molecular ferroelectrics may build up and enrich the content of ferroelectrochemistry.
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