Reduction-Responsive Cationic Vesicles from Bolaamphiphiles with Ionizable Amino Acid or Dipeptide Polar Heads.

This paper presents a study of the aggregation of cationic bolaamphiphilic molecules into vesicles. These molecules are based on a cystamine core with protonated terminal dipeptide groups. The study found that vesicles can be formed at pH 4 for all of the dipeptide-terminated bolaamphiphiles containing different combinations of l-valine, l-phenylalanine, and l-tryptophan. The concentration for aggregation onset was determined by using pyrene as a fluorescent probe or light dispersion for compounds with tryptophan. Dynamic light scattering (DLS) studies and transmission electron microscopy (TEM) reveal that the vesicles have diameters ranging from 140 to 500 nm and show the capability of loading hydrophobic cargos, such as Nile red, and their liberation in reductive environments. Furthermore, the bolaamphiphiles are only fully protonated and prone to vesicle formation at acidic pH, making them a promising alternative for gastrointestinal delivery.

Greenhouse Gas Emissions and Crossbred Cow Milk Production in a Silvopastoral System in Tropical Mexico.

In Mexico, pasture degradation is associated with extensive pastures; additionally, under these conditions, livestock activities contribute considerably to greenhouse gas (GHG) emissions. Among the options to improve grazing systems and reduce GHG emissions, silvopastoral systems (SPS) have been recommended. The objectives of this work were to quantify the N outflow in a soil-plant-animal interface, as well as the CH4 emissions and milk production in an SPS with woody legumes (Leucaena leucocephala) that is associated with stargrass (Cynodon nlemfuensis). This was then compared with stargrass in a monoculture system (MS) in the seasons (dry and rainy period) over a two-year period. Dung was collected from the animals of each of the grazing systems and applied fresh to the land plots. Fresh dung and urine were collected from the cows of each grazing system and were applied to the experimental plots. In addition, the soil CH4 and N2O contents were measured to quantify the emissions. Average milk yield by seasons was similar: MS (7.1 kg per animal unit (AU)/day-1) and SPS (6.31 kg per AU/day-1). Cows in the MS had a mean N intake of 171.9 g/UA day-1 without seasonal variation, while the SPS animals' mean N intake was 215.7 g/UA day-1 for both seasons. For the urine applied to soil, the N2O outflow was higher in the MS (peak value = 1623.9 µg N-N2O m-2 h-1). The peak value for the SPS was 755.9 µg of N-N2O m-2 h-1. The N2O emissions were higher in the rainy season (which promotes denitrification). The values for the feces treatment were 0.05% (MS) and 0.01% (SPS). The urine treatment values were 0.52% (MS) and 0.17% (SPS). The emissions of CH4 showed that the feces of the SPS systems resulted in a higher accumulation of gas in the rainy season (29.8 g C ha-1), followed by the feces of the MS system in the dry season (26.0 g C ha-1). Legumes in the SPS helped to maintain milk production, and the N2O emissions were lower than those produced by the MS (where the pastures were fertilized with N).

Gold nanoparticle-based two-photon fluorescent nanoprobe for monitoring intracellular nitric oxide levels.

Nitric oxide (NO) plays an important role in the regulation of the immune, cardiovascular and nervous systems. Consequently, being able to monitor and quantify intracellular NO levels would provide a greater understanding of the implications of this molecule in the different biological processes, including, for example, in cancer. Here, we report a broadly applicable two-photon excitable fluorescent nanoprobe able to detect and potentially quantify NO levels in an extensive range of cellular environments. The nanoprobe consists of a thiolated photoinduced electron transfer-based two=photon fluorescent probe attached onto the surface of 2.4 ± 0.7 nm gold nanoparticles (DANPY-NO@AuNPs). The nanoprobe, which can be synthesised in a reproducible manner and exhibits great stability when stored at room temperature, is able to selectively detect NO in solution, with a dynamic range up to 150 µM, and at pH values of biological relevance. DANPY-NO@AuNPs were able to selectively detect endogenous NO in RAW264.7γ NO- macrophages and THP-1 human leukemic cells; and endogenous and exogenous NO in endothelial cells. The nanoprobe accumulated in the acidic organelles of the tested cell lines showing negligible toxicity. Importantly, DANPY-NO@AuNPs showed potential to quantify intracellular NO concentrations in MDA-MB-231 breast cancer cells. The biological evaluation of the nanoprobe was undertaken using confocal laser scanning (images and intracellular emission spectra) and multiphoton microscopies, and flow cytometry. Based on their excellent sensitivity and stability, and outstanding versatility, DANPY-NO@AuNPs can be applied for the spatiotemporal monitoring of in vitro and in vivo NO levels.

Reduction-triggered Disassembly of Organic Cationic Nanorods Produces a Cysteine Protease Mimic (Miravet et†al.).

The emergence of catalytic activity associated with a disassembly process is reported, reminiscent of complex biological systems. A cystine derivative with pendant imidazole groups self-assembles into cationic nanorods in the presence of the cationic surfactants cetylpyridinium chloride (CPC) or cetyltrimethylammonium bromide (CTAB). Disulfide reduction triggers nanorod disassembly and the generation of a simple cysteine protease mimic, which shows a dramatically improved catalytic efficiency in the hydrolysis of p-nitrophenyl acetate (PNPA).

Enhancement of photoactivity and cellular uptake of (Bu4N)2[Mo6I8(CH3COO)6] complex by loading on porous MCM-41 support. Photodynamic studies as an anticancer agent.

The incorporation by ionic assembly of the hexanuclear molybdenum cluster (Bu4N)2[Mo6I8(CH3CO2)6] (1) in amino-decorated mesoporous silica nanoparticles MCM-41, has yielded the new molybdenum-based hybrid photosensitizer 1@MCM-41. The new photoactive material presents a high porosity, due to the intrinsic high specific surface area of MCM-41 nanoparticles (989 m2 g-1) which is responsible for the good dispersion of the hexamolybdenum clusters on the nanoparticles surface, as observed by STEM analysis. The hybrid photosensitizer can generate efficiently singlet oxygen, which was demonstrated by using the benchmark photooxygenation reaction of 9,10-anthracenediyl-bis(methylene)dimalonic acid (ABDA) in water. The photodynamic therapy activity has been tested using LED light as an irradiation source (λirr ~ 400-700 nm; 15.6 mW/cm2). The results show a good activity of the hybrid photosensitizer against human cervical cancer (HeLa) cells, reducing up to 70 % their viability after 20 min of irradiation, whereas low cytotoxicity is detected in the darkness. The main finding of this research is that the incorporation of molybdenum complexes at porous MCM-41 supports enhances their photoactivity and improves cellular uptake, compared to free clusters.

A highly photostable and versatile two-photon fluorescent probe for the detection of a wide range of intracellular nitric oxide concentrations in macrophages and endothelial cells.

Nitric oxide (NO) is involved in many biological processes affecting the cardiovascular, nervous and immune systems. Intracellular NO can be monitored using fluorescent probes in combination with fluorescence imaging techniques. Most of the currently available NO fluorescent molecular probes are excited via one-photon excitation using UV or Vis light, which results in poor penetration and high photodamage to living tissues. Here, we report a two-photon fluorescent molecular probe, DANPY-NO, able to detect NO in live cells. The probe consists of an o-phenylenediamine linked to a naphthalimide core; and operates via photoinduced electron transfer. DANPY-NO exhibits good sensitivity (LOD of 77.8 nM) and high selectivity towards NO, and is stable over a broad range of pHs. The probe targeted acidic organelles within macrophages and endothelial cells, and demonstrated enhanced photostability over a commercially available NO probe. DANPY-NO was used to selectively detect endogenous NO in RAW264.7ϒ NO- macrophages, THP-1 human leukemic cells, primary mouse (bone marrow-derived) macrophages and endothelial cells. The probe was also able to detect exogenous NO in endothelial cells and distinguish between increasing concentrations of NO. The NO detection was evidenced using confocal laser scanning and two-photon microscopies, and flow cytometry. Further evidence was obtained by recording the changes in the intracellular fluorescence emission spectrum of the probe. Importantly, the probe displayed negligible toxicity to the analysed biological samples. The excellent sensitivity, selectivity, stability and versatility of DANPY-NO confirm its potential for in vitro and in vivo imaging of NO.

Glutathione-responsive molecular nanoparticles from a dianionic bolaamphiphile and their use as carriers for targeted delivery.

The formation in aqueous media of molecular nanoparticles from a bolaamphiphile (SucIleCsa) incorporating a disulfide moiety is described. The particles can be loaded efficiently with the lipophilic mitochondrial marker DiOC6(3), quenching its fluorescence, which is recovered upon reductive particle disassembly. DiOC6(3) transport into human colorectal adenocarcinoma cells (HT-29) is demonstrated using flow cytometry and confocal scanning fluorescence microscopy. A significant increase in intracellular fluorescence is observed when the cells are stimulated to produce glutathione (GSH). These new molecular nanoparticles can be considered a theranostic tool that simultaneously achieves targeted delivery of lipophilic substances and signals high levels of GSH.

Detection of subcellular nitric oxide in mitochondria using a pyrylium probe: assays in cell cultures and peripheral blood.

Fluorescent probes for the detection of intracellular nitric oxide (NO) are abundant, but those targeted to the mitochondria are scarce. Among those molecules targeting mitochondrial NO (mNO), the majority use a triphenylphosphonium (TPP) cation as a vector to reach such organelles. Here we describe a simple molecule (mtNOpy) based on the pyrylium structure, made in a few synthetic steps, capable of detecting selectively NO (aerated medium) over other reactive species. The calculated detection limit for mtNOpy is 88 nM. The main novelty of this probe is that it has a simple molecular architecture and can act both as a fluorogenic and as a mitochondriotropic agent, without using TPP. mtNOpy has been tested in two different scenarios: (a) in a controlled environment of cell line cultures (human colon carcinoma HT-29 cells and mouse macrophage RAW 264.7 cells), using confocal laser scanning microscopy, and (b) on a much more complex sample of peripheral blood, using flow cytometry. In the first context, mtNOpy has been found to be responsive (turn-on fluorescence) to exogenous and endogenous NO stimuli (via SNAP donor and LPS stimulation, respectively). In the second area, mtNOpy has been able to discriminate between NO-generating phagocytes (neutrophils and monocytes) from other leukocytes (NK, B and T cells).

Fluorescent styrylpyrylium probes for the imaging of mitochondria in live cells.

Eight styrylpyrylium tetrafluoroborate salts have been synthesized and fully optically characterized by UV-vis absorption and fluorescence steady-state/time-resolved spectroscopies. The new dyes exhibit strong emission bands with yellow-orange colours, depending on the substituents present in the structure. Notably, the Stokes shift recorded for some of them exceeds 100 nm, a very valuable feature for biological imaging. Four of them have been assayed as biological imaging agents by confocal laser scanning microscopy (CLSM) in the human hepatoma cell line Hep3B. It has been found that all the compounds efficiently stain intracellular structures which have been identified as mitochondria through colocalization assays with MitoView (a well-known mitochondrial marker) and using carbonyl cyanide m-chlorophenyl hydrazone (CCCP) as a mitochondrial membrane potential uncoupler. Additionally, the potential ability of the studied dyes as cytotoxic drugs has been explored. The inhibitory concentration (IC50) against Hep3B was found to be in the range of 4.2 µM-11.5 µM, similar to other described anticancer drugs for the same hepatoma cell line. The combined features of a good imaging agent and potential anticancer drug make the family of the studied pyrylium salts good candidates for further theranostic studies. Remarkably, despite the extensive use of pyrylium dyes in several scientific areas (from photocatalysis to optics), there is no precedent description of a styrylpyrylium salt with potential theranostic applications.

Corrección de una clase III esqueletal con anclaje óseo en paciente en crecimiento: Reporte de caso / Skeletal class III correction in growing patient with bone anchorage: CaseReport

Antecedentes: La clase III esqueletal, es una deformidad dentofacial donde el tercio inferior de la cara es más prominente, el tratamiento se decide según la etiología y la edad del paciente; si se encuentra en crecimiento la malformación puede ser tratada con un protocolo interceptivo y si es posible evitar la cirugía ortognática a futuro. Objetivo: Mejorar la clase esqueletal, descruzar la mordida u obtener mordida borde a borde, mejorar la posición del labio superior y evaluar el comparativo inicial-final de SNA y ANB. Reporte de caso:Paciente masculino de 13 años, sin antecedentes personales patológicos o familiares reportados; presenta clase III esqueletal responsiva bimaxilar, crecimiento vertical, clase molar I y canina III; fue tratado con el protocolo de mini placas BAMP (bone anchored maxillary protraction) por sus siglas en inglés, elásticos intermaxilares y un paladar con pistas planas. Resultados:La fase ortopédica duro cinco meses y se logró mordida borde a borde y clase I esqueletal. Discusión: Se obtuvieron resultados con el uso de mini implantes sin anclaje extraoral en menos tiempo a comparación de otros métodos que tienen que ser usados por 9-12 meses.Conclusión:El protocolo BAMP puede ser usado en pacientes en crecimiento sin máscara facial para corregir la clase III esqueletal.

Background: Skeletal class III is a dentofacial deformity where the lower third ofthe face is more prominent. The treatment is decided according to the etiology and age of the patient; If the patient is in growing, the malformation can be treated with an interceptive protocol and if possible, avoid a orthognathic surgery in the future. Objective: Improve the skeletal class, uncross the bite or obtain an edge-to-edge bite, improve the position of the upper lip and compare the initial-final relationship of ANS and ANB.Case report:13-year-old male patient, with no reported pathological or family history; presents skeletal class III, vertical growth, molar class I and canine III; he was treated with the protocol of mini BAMP (bone anchored maxillary protraction) plates, intermaxillary elastics and a palate with flat tracks. Results:The orthopedic phase lasted five months and an edge-to-edge bite and skeletal class I were achieved.Discussion:Results were obtained with the use of mini plates without extraoralanchorage in less time compared to other methods that have to be used for 9-12 months. Conclusion: The BAMP protocol can be used in growing patients without a face mask to correct skeletal class III.

Non-Polymeric Nanogels as Versatile Nanocarriers: Intracellular Transport of the Photosensitizers Rose Bengal and Hypericin for Photodynamic Therapy.

The use of nanocarriers for intracellular transport of actives has been extensively studied in recent years and represents a central area of nanomedicine. The main novelty of this paper lies on the use of nanogels formed by a low-molecular-weight gelator (1). Here, non-polymeric, molecular nanogels are successfully used for intracellular transport of two photodynamic therapy (PDT) agents, Rose Bengal (RB) and hypericin (HYP). The two photosensitizers (PSs) exhibit different drawbacks for their use in clinical applications. HYP is poorly water-soluble, while the cellular uptake of RB is hindered due to its dianionic character at physiological pH values. Additionally, both PSs tend to aggregate precluding an effective PDT. Despite the different nature of these PSs, nanogels from gelator 1 provide, in both cases, an efficient intracellular transport into human colon adenocarcinoma cells (HT-29) and a notably improved PDT efficiency, as assessed by confocal laser scanning microscopy and flow cytometry. Furthermore, no significant dark toxicity of the nanogels is observed, supporting the biocompatibility of the delivery system. The developed nanogels are highly reproducible due to their non-polymeric nature, and their synthesis is easily scaled up. The results presented here thus confirm the potential of molecular nanogels as valuable nanocarriers, capable of entrapping both hydrophobic and hydrophilic actives, for PDT of cancer.

Martian dust storm impact on atmospheric H2O and D/H observed by ExoMars Trace Gas Orbiter.

Global dust storms on Mars are rare1,2 but can affect the Martian atmosphere for several months. They can cause changes in atmospheric dynamics and inflation of the atmosphere3, primarily owing to solar heating of the dust3. In turn, changes in atmospheric dynamics can affect the distribution of atmospheric water vapour, with potential implications for the atmospheric photochemistry and climate on Mars4. Recent observations of the water vapour abundance in the Martian atmosphere during dust storm conditions revealed a high-altitude increase in atmospheric water vapour that was more pronounced at high northern latitudes5,6, as well as a decrease in the water column at low latitudes7,8. Here we present concurrent, high-resolution measurements of dust, water and semiheavy water (HDO) at the onset of a global dust storm, obtained by the NOMAD and ACS instruments onboard the ExoMars Trace Gas Orbiter. We report the vertical distribution of the HDO/H2O ratio (D/H) from the planetary boundary layer up to an altitude of 80 kilometres. Our findings suggest that before the onset of the dust storm, HDO abundances were reduced to levels below detectability at altitudes above 40 kilometres. This decrease in HDO coincided with the presence of water-ice clouds. During the storm, an increase in the abundance of H2O and HDO was observed at altitudes between 40 and 80 kilometres. We propose that these increased abundances may be the result of warmer temperatures during the dust storm causing stronger atmospheric circulation and preventing ice cloud formation, which may confine water vapour to lower altitudes through gravitational fall and subsequent sublimation of ice crystals3. The observed changes in H2O and HDO abundance occurred within a few days during the development of the dust storm, suggesting a fast impact of dust storms on the Martian atmosphere.

Publisher Correction: Martian dust storm impact on atmospheric H2O and D/H observed by ExoMars Trace Gas Orbiter.

The surname of author Cathy Quantin-Nataf was misspelled 'Quantin-Nata' , authors Ehouarn Millour and Roland Young were missing from the ACS Science Team list, and minor changes have been made to the author and affiliation lists; see accompanying Amendment. These errors have been corrected online.

Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation.

In the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans loss-of-function mutants for the glutathione reductase gsr-1 gene enhance the deleterious phenotypes of heterologous human, as well as endogenous worm aggregation-prone proteins. These effects are phenocopied by the GSH-depleting agent diethyl maleate. Additionally, gsr-1 mutants abolish the nuclear translocation of HLH-30/TFEB transcription factor, a key inducer of autophagy, and strongly impair the degradation of the autophagy substrate p62/SQST-1::GFP, revealing glutathione reductase may have a role in the clearance of protein aggregates by autophagy. Blocking autophagy in gsr-1 worms expressing aggregation-prone proteins results in strong synthetic developmental phenotypes and lethality, supporting the physiological importance of glutathione reductase in the regulation of misfolded protein clearance. Furthermore, impairing redox homeostasis in both yeast and mammalian cells induces toxicity phenotypes associated with protein aggregation. Together, our data reveal that glutathione redox homeostasis may be central to proteostasis maintenance through autophagy regulation.

Synthesis, spectroscopic studies and biological evaluation of acridine derivatives: The role of aggregation on the photodynamic efficiency.

Two new photoactive compounds (1 and 2) derived from the 9-amidoacridine chromophore have been synthesized and fully characterized. Their abilities to produce singlet oxygen upon irradiation have been compared. The synthesized compounds show very different self-aggregating properties since only 1 present a strong tendency to aggregate in water. Biological assays were conducted with two cell types: hepatoma cells (Hep3B) and human umbilical vein endothelial cells (HUVEC). Photodynamic therapy (PDT) studies carried out with Hep3B cells showed that non-aggregating compound 2 showed photoxicity, ascribed to the production of singlet oxygen, being aggregating compound 1 photochemically inactive. On the other hand suspensions of 1, characterized as nano-sized aggregates, have notable antiproliferative activity towards this cell line in the dark.

Sizing Down a Supramolecular Gel into Micro- and Nanoparticles.

A low molecular weight gelator with a fluorescent 1,8-naphthalimide unit forms micro- and nanoparticles in aqueous media. Slow addition of a DMSO solution of the gelator into water affords either a self-assembled fibrillar network, sheaf-like microparticles, or nanoparticles depending to the concentration used in the experiment. The micro- and nanoparticles were characterized by dynamic light scattering (DLS), electron microscopy, and fluorescence measurements. In an initial assay of particle loading, Rose Bengal and Rhodamine 123 were shown to be incorporated in the particles. Light-promoted singlet oxygen generation capabilities of Rose Bengal were modulated by its incorporation in the particles. Additionally, the particles were found to promote the transport of Rhodamine 123 into human lung carcinoma live cells. These results indicate that nanoparticles arising from low molecular weight gelators may represent a new type of nanocarriers, being a potential alternative to polymeric nanogels used in nanomedicine.

Thermally Regulated Reversible Formation of Vesicle-Like Assemblies by Hexaproline Amphiphiles.

Peptides composed of hexaproline and glutamic acid (P6E) or lysine (P6K) as C-terminal units show thermally promoted aggregation, affording vesicle-like assemblies upon heating to 80 °C. The aggregation is analyzed by dynamic light scattering (DLS), with number-averaged diameters of ca. 600 and 300 nm, respectively, for P6E and P6K. NMR studies reveal that upon heating the amount of NMR-visible species is reduced to ca. 50% and that an important conformational change is experienced by the molecules in solution. Circular dichroism (CD) shows that at 20 °C the peptides present a polyproline II (PP-II) conformation which is disorganized upon heating. Scanning electron microscopy for samples which were fast frozen at 80 °C reveals vesicle-like assemblies. Using pyrene as a fluorescence probe, a critical aggregation concentration of ca. 30 µM was estimated for P6E, while that of P6K was above 0.6 mM. The aggregation process is found to be fully reversible and could serve as a basis for development of stimuli responsive carriers.

Glutathione reductase gsr-1 is an essential gene required for Caenorhabditis elegans early embryonic development.

Glutathione is the most abundant thiol in the vast majority of organisms and is maintained in its reduced form by the flavoenzyme glutathione reductase. In this work, we describe the genetic and functional analysis of the Caenorhabditis elegans gsr-1 gene that encodes the only glutathione reductase protein in this model organism. By using green fluorescent protein reporters we demonstrate that gsr-1 produces two GSR-1 isoforms, one located in the cytoplasm and one in the mitochondria. gsr-1 loss of function mutants display a fully penetrant embryonic lethal phenotype characterized by a progressive and robust cell division delay accompanied by an aberrant distribution of interphasic chromatin in the periphery of the cell nucleus. Maternally expressed GSR-1 is sufficient to support embryonic development but these animals are short-lived, sensitized to chemical stress, have increased mitochondrial fragmentation and lower mitochondrial DNA content. Furthermore, the embryonic lethality of gsr-1 worms is prevented by restoring GSR-1 activity in the cytoplasm but not in mitochondria. Given the fact that the thioredoxin redox systems are dispensable in C. elegans, our data support a prominent role of the glutathione reductase/glutathione pathway in maintaining redox homeostasis in the nematode.

The synthesis of new fluorescent bichromophoric compounds as ratiometric pH probes for intracellular measurements.

Three different bichromophoric compounds (1-3) containing an aminomethyl anthracene moiety linked to a second chromophore (pyrene, 4-nitrobenzo-2-oxa-1,3-diazole (NBD) and dansyl) through a valine-derived pseudopeptidic spacer have been prepared and their fluorescent properties studied. The results obtained show that upon irradiation the photophysical behavior of these probes involves electronic energy transfer from the excited anthracene to the second chromophore and also intramolecular photoinduced electron transfer. The X-ray structure obtained for 3 reveals that the folding associated with the pseudopeptidic spacer favours a close proximity of the two chromophores. The emissive response of 3 is clearly dependent on the pH of the medium, hence this bichromophoric compound was shown to be an excellent ratiometric pH fluorescent sensor. The emission intensity due to the anthracene moiety exhibits a decrease at neutral-basic pH values that is concomitant with an increase in the intensity arising from the dansyl fluorophore. These properties make this compound a good candidate for biological pH sensing as has been confirmed by preliminary studies with RAW 264.7 macrophage cells imaged by means of confocal fluorescence microscopy with an average pH estimation of 5.4-5.8 for acidic organelles.

Protective role of DNJ-27/ERdj5 in Caenorhabditis elegans models of human neurodegenerative diseases.

AIMS: Cells have developed quality control systems for protection against proteotoxicity. Misfolded and aggregation-prone proteins, which are behind the initiation and progression of many neurodegenerative diseases (ND), are known to challenge the proteostasis network of the cells. We aimed to explore the role of DNJ-27/ERdj5, an endoplasmic reticulum (ER)-resident thioredoxin protein required as a disulfide reductase for the degradation of misfolded proteins, in well-established Caenorhabditis elegans models of Alzheimer, Parkinson and Huntington diseases. RESULTS: We demonstrate that DNJ-27 is an ER luminal protein and that its expression is induced upon ER stress via IRE-1/XBP-1. When dnj-27 expression is downregulated by RNA interference we find an increase in the aggregation and associated pathological phenotypes (paralysis and motility impairment) caused by human ß-amyloid peptide (Aß), α-synuclein (α-syn) and polyglutamine (polyQ) proteins. In turn, DNJ-27 overexpression ameliorates these deleterious phenotypes. Surprisingly, despite being an ER-resident protein, we show that dnj-27 downregulation alters cytoplasmic protein homeostasis and causes mitochondrial fragmentation. We further demonstrate that DNJ-27 overexpression substantially protects against the mitochondrial fragmentation caused by human Aß and α-syn peptides in these worm models. INNOVATION: We identify C. elegans dnj-27 as a novel protective gene for the toxicity associated with the expression of human Aß, α-syn and polyQ proteins, implying a protective role of ERdj5 in Alzheimer, Parkinson and Huntington diseases. CONCLUSION: Our data support a scenario where the levels of DNJ-27/ERdj5 in the ER impact cytoplasmic protein homeostasis and the integrity of the mitochondrial network which might underlie its protective effects in models of proteotoxicity associated to human ND.