Biology subjects

Nechushtai, R.

Publications and source records attributed to Nechushtai, R..

6 recordsLinked to original sources

bioRxiv2025

Unraveling the molecular mechanism underlying the anticancer activity of CISD2/NAF-144-67

We recently reported on the development of a unique cancer-targeting peptide called NAF-144-67 (derived from CISD2/NAF-1). NAF-144-67 selectively permeates the plasma membrane (PM) of cancer cells, but not healthy cells, causing the activation of apoptotic and ferroptotic cell death pathways specifically in cancer cells. NAF-144-67 also targets and shrinks human breast and ovarian cancer tumors in a xenograft mice model system without any apparent side effects. Although the specific permeation of NAF-144-67 through cancer cell PMs was studied, and its cancer killing effects validated in vitro and in vivo, little is known about how NAF-144-67 exerts its biological activity once it enters cancer cells. Here, we report that NAF-144-67 targets the CISD2/NAF-1 protein of cancer cells and disrupts its homodimeric structure. We further reveal that a peptide derived from the same domain of the human CISD1 (mitoNEET; mNT19-42) protein, a close family member to CISD2, has no killing activity towards cancer cells, and that dimers of NAF-144-67 (at two different orientations) have higher anticancer activity compared to monomeric NAF-144-67. Our findings shed new light on the biological activity of NAF-144-67 and bring it closer to becoming a potential new anticancer drug.

cancer biology↗

bioRxiv2024

Targeting primary and metastatic ovarian cancer with a peptide derived from the human NAF-1/CISD2 protein

Ovarian cancer is the most fatal cancer of female reproductive organs. Ovarian cancer is typically diagnosed at a late stage, after metastasis occurred, leading to a 5-years relative survival rate of only [~]5%. Here, we demonstrate the anti-ovarian cancer properties of a peptide derived from the human protein CISD2/NAF-1 (3D-NAF-144-67-6K). This peptide selectively permeates the plasma membrane of ovarian cancer SKOV-3 cells without affecting healthy cells. 3D-NAF-144-67-6K targets and destroys the cancer cells mitochondria which leads to cancer cell death. In vivo studies of mice carrying xenograft tumours of SKOV-3 showed that the peptide significantly decreased the overall size and growth rate of both primary and metastatic ovarian cancer tumours. We further show that 3D-NAF-144-67-6K has a broad-spectrum anticancer activity targeting leukaemia, brain, and pancreas cancer cells. Our study suggests that 3D-NAF-144-67-6K could be used, alone or in drug combinations, to treat ovarian cancer and improve patient survival.

cancer biology↗

bioRxiv2023

CISD3 is required for Complex I function, mitochondrial integrity, and skeletal muscle maintenance

Mitochondria play a central role in muscle metabolism and function. In skeletal muscles, a unique family of iron-sulfur proteins, termed CISD proteins, support mitochondrial function. The abundance of these proteins declines with aging leading to muscle degeneration. Although the function of the outer mitochondrial proteins CISD1 and CISD2 has been defined, the role of the inner mitochondrial protein CISD3, is currently unknown. Here we show that CISD3 deficiency in mice results in muscle atrophy that shares proteomic features with Duchenne Muscular Dystrophy. We further reveal that CISD3 deficiency impairs the function and structure of skeletal muscle mitochondria, and that CISD3 interacts with, and donates its clusters to, Complex I respiratory chain subunit NDUFV2. These findings reveal that CISD3 is important for supporting the biogenesis and function of Complex I, essential for muscle maintenance and function. Interventions that target CISD3 could therefore impact muscle degeneration syndromes, aging, and related conditions.

cell biology↗

bioRxiv2022

The cluster transfer function of AtNEET supports the ferredoxin-thioredoxin network of plant cells

NEET proteins are conserved 2Fe-2S proteins that regulate the levels of iron and reactive oxygen species in plant and mammalian cells. Previous studies of seedlings with constitutive expression of AtNEET, or its dominant-negative variant H89C (impaired in 2Fe-2S cluster transfer), revealed that disrupting AtNEET function causes oxidative stress, chloroplast iron overload, activation of iron-deficiency responses, and cell death. Because disrupting AtNEET function is deleterious to plants, we developed an inducible expression system to study AtNEET function in mature plants using a time-course proteomics approach. Here, we report that suppression of AtNEET cluster transfer function results in drastic changes in the expression of different members of the ferredoxin (Fd), Fd-thioredoxin (TRX) reductase (FTR), and TRX network of Arabidopsis, as well as in cytosolic cluster assembly proteins. In addition, the expression of Yellow Stripe-Like 6 (YSL6), involved in iron export from chloroplasts was elevated. Taken together, our findings reveal new roles for AtNEET in supporting the Fd-TFR-TRX network of plants, iron mobilization from the chloroplast, and cytosolic 2Fe-2S cluster assembly. In addition, we show that AtNEET function is linked to the expression of glutathione peroxidases (GPXs) which play a key role in the regulation of ferroptosis and redox balance in different organisms. HighlightUsing proteomics analysis and an inducible expression system, the iron-sulfur cluster transfer function of AtNEET was found to support the ferredoxin-thioredoxin network of Arabidopsis.

plant biology↗

bioRxiv2020

The impact of multifactorial stress combination on plant growth and survival

O_LIClimate change-driven extreme weather events, combined with increasing temperatures, harsh soil conditions, low water availability and quality, and the introduction of many man-made pollutants, pose a unique challenge to plants. Although our knowledge of the response of plants to each of these individual conditions is vast, we know very little about how a combination of many of these factors, occurring simultaneously, i.e., multifactorial stress combination, impacts plants. C_LIO_LISeedlings of wild type and different mutants of Arabidopsis thaliana plants were subjected to a multifactorial stress combination of six different stresses, each applied at a low level, and their survival, physiological and molecular responses determined. C_LIO_LIOur findings reveal that while each of the different stresses, applied individually, had a negligible effect on plant growth and survival, the accumulated impact of multifactorial stress combination on plants was detrimental. We further show that the response of plants to multifactorial stress combination is unique and that specific pathways and processes play a critical role in the acclimation of plants to multifactorial stress combination. C_LIO_LITaken together our findings reveal that further polluting our environment could result in higher complexities of multifactorial stress combinations that in turn could drive a critical decline in plant growth and survival. C_LI Plain Language SummaryThe effects of multiple stress conditions occurring simultaneously, i.e., multifactorial stress combination, on plants is currently unknown. Here we show that different co-occurring stresses can interact to negatively impact plant growth and survival, even if the effect of each individual stress is negligible. We further identify several key pathways essential for plant acclimation to multifactorial stress combination.

plant biology↗

bioRxiv2020

Cadmium interference with iron sensing reveals transcriptional programs sensitive and insensitive to reactive oxygen species

Iron (Fe) is an essential micronutrient whose uptake is tightly regulated to prevent either deficiency or oxidative stress. Cadmium (Cd) is a non-essential heavy metal that induces both Fe-deficiency and oxidative stress; however, the mechanisms underlying these Cd-induced responses are still elusive. Here we explored Cd-induced Fe-associated responses in wildtype Arabidopsis and opt3-2, a mutant that over-accumulates Fe. Gene expression profiling revealed a large overlap between transcripts induced by Fe-deficiency and Cd exposure in wildtype plants and the opt3 mutant. Interestingly, vascular-localized Fe-responsive genes were found to be highly induced by Cd even in the presence of high Fe and H2O2 levels, suggesting that Cd impairs Fe sensing. It was recently shown that Fe-S cluster-containing proteins AtNEET, play a role in Fe sensing. Our data shows that Cd negatively impacts both the stability and Fe-S transfer activity of AtNEET. Altogether, our data indicate that Fe-deficiency responses are governed by multiple inputs and that a hierarchical regulation of Fe-deficiency responses prevents the induction of specific gene networks when Fe and H2O2 levels are high. Other Cd/Fe-responsive genes however, are insensitive to this negative feedback regulation suggesting that their induction is the result of an impaired Fe sensing as opposed to the traditional view of Cd/Fe uptake competition at the root level.Highlight Cadmium induces an iron-deficiency response often explained by root uptake competition; here we show that Cd also impairs Fe sensing in leaves, even when Fe is in sufficient quantities.Competing Interest StatementThe authors have declared no competing interest.View Full Text

plant biology↗