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Chemotherapy resistance in triple-negative breast cancer (TNBC) leads to poor therapeutic effects and a poor prognosis. Given that paclitaxel-based chemotherapy is the main treatment method for TNBC, enhancing its chemosensitivity has been a research focus. Induced ferroptosis of tumour cells has been proven to increase chemosensitivity, but its ability to sensitize TNBC cells to paclitaxel (PTX) is unknown. In our experiments, measurements of viability and proliferation validated the synergistic effect of PTX combined with RSL3 on TNBC cells. The accumulation of intracellular Fe2+ and lipid reactive oxygen species, as well as the expression of malondialdehyde, illustrated that RSL3 enhanced the chemosensitivity of TNBC to PTX by inducing ferroptosis. Through transcriptome sequencing, a series of differentially expressed genes were identified, in which the expression of cytokines, such as CXCLs, was significantly increased in the treatment group, and the effect of combination therapy on TNBC was enriched mainly in the NFκB signalling pathway. In subsequent validation experiments, the use of the NF-κB inhibitor BAY11-7082 reversed the inhibitory effects of PTX and RSL3 on TNBC cell activity. In a xenograft immunodeficient mouse model, the inhibitory effects of PTX and RSL3 on TNBC in vivo were further verified. Our research validated the synergistic effects of PTX and RSL3 both in vivo and in vitro, with RSL3 inducing ferroptosis by activating the NF-κB signalling pathway, thereby increasing the chemosensitivity of TNBC to PTX. This study provides new insights for improving the therapeutic efficacy of treatment strategies. Show less

Serpentinizing hydrothermal vents are likely sites for the origin of metabolism because they produce H2 as a source of electrons for CO2 reduction while depositing zero-valent iron, cobalt, and nickel as catalysts for organic reactions. Recent work has shown that solid-state nickel can catalyze the H2-dependent reduction of CO2 to various organic acids and their reductive amination with H2 and NH3 to biological amino acids under the conditions of H2-producing hydrothermal vents and that amino acid synthesis from NH3, H2, and 2-oxoacids is facile in the presence of Ni0. Such reactions suggest a metallic origin of metabolism during early biochemical evolution because single metals replace the function of over 130 enzymatic reactions at the core of metabolism in microbes that use the acetyl-CoA pathway of CO2 fixation. Yet solid-state catalysts tether primordial amino synthesis to a mineral surface. Many studies have shown that pyridoxal catalyzes transamination reactions without enzymes. Here we show that pyridoxamine, the NH2-transferring intermediate in pyridoxal-dependent transamination reactions, is generated from pyridoxal by reaction with NH3 (as little as 5 mm) and H2 (5 bar) on Ni0 as catalyst at pH 11 and 80 °C within hours. These conditions correspond to those in hydrothermal vents undergoing active serpentinization. The results indicate that at the origin of metabolism, pyridoxamine provided a soluble, organic amino donor for aqueous amino acid synthesis, mediating an evolutionary transition from NH3-dependent amino acid synthesis on inorganic surfaces to pyridoxamine-dependent organic reactions in the aqueous phase. Show less

Lipid peroxidation stands as a prominent hallmark and a prerequisite for the onset of ferroptosis. Lipid metabolism holds a pivotal role in regulating this process, forming the metabolic foundation for cellular sensitivity to ferroptosis. Studies in lipid metabolomics reveal that the activation of Polyunsaturated fatty acids (PUFA), specifically arachidonic acid and adrenoic acid (AdA), mediated by acyl-CoA synthetase long-chain family member 4 (ACSL4), represents a critical step in generating lipid peroxidation substrates. The expression level or enzymatic activity of ACSL4 emerges as a potential indicator of cellular susceptibility to ferroptosis. Additionally, other members of the ACSL family can indirectly influence the occurrence of ferroptosis by modifying the fatty acid composition of the cell membrane. Given the high expression of ACSL4 in various human tumors, targeting lipid peroxidation with ACSL4 as the focal point may pave a new path in tumor therapy. This article provides a brief overview of the primary structure and function of ACSL4, its role in lipid peroxidation, and summarizes the current advancements in drug development targeting ACSL4 and lipid peroxidation. Show less

Iron-sulfur (Fe-S) clusters are critical cofactors in metalloproteins, essential for cellular processes such as energy production, DNA repair, enzymatic catalysis, and metabolic regulation. While Fe-S cluster functions are intimately linked to their redox properties, their precise roles in many proteins remain unclear. In this study, we present a regression model based on experimental redox potential (E m ) data, utilizing only two features: the Fe-S cluster's total charge and the Fe atoms' average valence. This model achieves a high correlation with experimental data (R 2 = 0.82) and an average prediction error of 0.12 V. Applying this model across the Protein Data Bank, we predict E m values for all cataloged Fe-S clusters, uncovering redox potential trends across diverse cluster classes. The computed redox potentials showed strong agreement with experimental values, achieving an overall accuracy of 88%. This streamlined, computationally accessible approach enhances the annotation and mechanistic understanding of Fe-S proteins, offering new insights into the redox variability of electron transport proteins. Our model holds promise for advancing studies of metalloprotein function and facilitating the design of bioinspired redox systems. Show less

Ferroptosis is a non-apoptotic type of cell death that is induced by uncontrolled iron-dependent phospholipid peroxidation and has important roles in disease. This Expert Recommendation article summarizes ferroptosis regulation and mechanisms and provides recommendations to increase the reproducibility and robustness of ferroptosis research. Show less

Electron transfer coupled to redox chemistry is at the heart of metabolism. The proteins responsible for moving electrons (protein electron carriers) must have emerged at the origin of life. The small iron-sulfur-binding bacterial ferredoxins were likely among these first proteins. Embedded within the ferredoxin sequence and structure is a symmetry that points to an ancient gene duplication event. Little is understood about the nature of ferredoxins prior to this duplication event or what environmental factors may have driven the selection for more complex forms. The deep-time molecular history of ferredoxins goes back billions of years and cannot be reconstructed by phylogenetic analyses based on amino acid sequences. Here, we use structure-guided protein design to model a fossil half-ferredoxin stage in the evolution of this fold, the semidoxins, and their symmetric full-length counterparts, the symdoxins. Semidoxin designs homodimerize, exhibiting structural, thermodynamic, and electrochemical behaviors in most cases identical to cognate symdoxins. However, the semi- and symdoxin fossil stages behave differently when incorporated into an in vivo electron transfer complementation assay. Both can support bacterial growth dependent on protein expression. Growth rates of bacteria expressing the semidoxins are much more sensitive to oxygen than those of bacteria expressing symdoxins. Motivated by the in vivo functionality of designed semidoxins, we identified putative naturally occurring semidoxins in extant anaerobic microorganisms. This is consistent with the observed in vivo oxygen sensitivity of the semidoxin designs. One natural semidoxin is shown to be folded and redox active. However, it exists as a mixture of monomers and dimers, suggesting a potential connection between semidoxins and even simpler single iron-sulfur cluster-binding peptides. Show less

Molecular hydrogen is the electron donor for the ancient exergonic reductive acetyl-coenzyme A pathway (acetyl-CoA pathway), which is used by hydrogenotrophic methanogenic archaea. How the presence of iron-sulfides influenced the acetyl-CoA pathway under primordial early Earth geochemistry is still poorly understood. Here we show that the iron-sulfides mackinawite (FeS) and greigite (Fe3S4), which formed in chemical garden experiments simulating geochemical conditions of the early Archaean eon (4.0-3.6 billion years ago), produce abiotic H2 in sufficient quantities to support hydrogenotrophic growth of the hyperthermophilic methanogen Methanocaldococcus jannaschii. Abiotic H2 from iron-sulfide formation promoted CO2 fixation and methanogenesis and induced overexpression of genes encoding the acetyl-CoA pathway. We demonstrate that H2 from iron-sulfide precipitation under simulated early Earth hydrothermal geochemistry fuels a H2-dependent primordial metabolism. Show less

FSP1 is a key suppressor of lipid peroxidation and ferroptosis, yet it is largely dispensable in standard cell culture models. Two new studies now show that FSP1 becomes essential for tumour growth in vivo, establishing it as a context-specific cancer vulnerability and highlighting the therapeutic potential of FSP1 inhibition. Show less

Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment. Show less

Sassano et al. identify endoplasmic reticulum–mitochondria contact sites as the intracellular location where phospholipid peroxidation first occurs to promote ferroptosis. Manipulating these contact sites dictates ferroptosis sensitivity in breast cancer. Show less

Geological structures known as alkaline hydrothermal vents (AHVs) likely displayed dynamic energy characteristics analogous to cellular chemiosmosis and contained iron-oxyhydroxide green rusts in the early Earth. Under specific conditions, those minerals could have acted as non-enzymatic catalysts in the development of early bioenergetic chemiosmotic energy systems while being integrated into the membrane of AHV-produced organic vesicles. Here, we show that the simultaneous addition of two probable AHV components, namely nickel and amino acids, impacts green rust's physico-chemical properties, especially those required for its incorporation in lipid vesicle's membranes, such as decreasing the mineral size to the nanometer scale and increasing its hydrophobicity. These results suggest that such hydrophobic nano green rusts could fit into lipid vesicle membranes and could have functioned as a primitive, inorganic precursor to modern chemiosmotic metalloenzymes, facilitating both electron and proton transport in early life-like systems. Show less

Ferredoxins (FDXs) are evolutionarily conserved iron-sulfur (Fe-S) proteins that serve as master regulators of mitochondrial redox homeostasis, governing critical processes including electron transfer, energy metabolism, Fe-S cluster biogenesis, and steroidogenesis. In humans, the mitochondrial isoforms FDX1 and FDX2 exhibit specialized yet complementary functions: FDX1 directs steroidogenesis, protein lipoylation, and copper redox cycling, while FDX2 is a core factor in Fe-S cluster assembly. Crucially, dysregulation of these proteins disrupts mitochondrial integrity, impairs redox balance, and activates multiple programmed cell death (PCD) pathways such as cuproptosis, ferroptosis, apoptosis, and autophagic cell death. This review systematically analyzes their isoform-specific roles in mitochondrial electron transport, Fe-S cluster dynamics, metabolic regulation, and summarizes major advances in understanding how FDX1 and FDX2 orchestrate mitochondrial-PCD crosstalk. The work further examines their critical functions in PCD execution, including FDX1-mediated cuproptosis through Cu+-dependent aggregation of lipoylated proteins and FDX2-deficiency-driven ferroptosis via Fe-S cluster collapse and iron overload. Disease mechanisms across multiple pathologies, including cancer, neurodegeneration, cardiovascular disease, endocrine disorders, and genetic syndromes, are explored, highlighting links to FDX dysfunction, with emerging therapeutic strategies targeting FDXs also addressed. By elucidating the synergistic roles of FDX1 and FDX2 as metabolic-death gatekeepers, this review establishes a foundation for developing isoform-targeted therapies against diverse pathologies. Show less

N-acetyl-l-cysteine (NAC) is a medication and a widely used antioxidant in cell death research. Despite its somewhat obscure mechanism of action, its role in inhibiting ferroptosis is gaining increasing recognition. In this study, we demonstrate that NAC treatment rapidly replenishes the intracellular cysteine pool, reinforcing its function as a prodrug for cysteine. Interestingly, its enantiomer, N-acetyl-d-cysteine (d-NAC), which cannot be converted into cysteine, also exhibits a strong anti-ferroptotic effect. We further clarify that NAC, d-NAC, and cysteine all act as direct reducing substrates for GPX4, counteracting lipid peroxidation. Consequently, only GPX4-rather than system xc-, glutathione biosynthesis, or ferroptosis suppressor protein 1-is necessary for NAC and d-NAC to prevent ferroptosis. Additionally, we identify a broad range of reducing substrates for GPX4 in vitro, including β-mercaptoethanol. These findings provide new insights into the mechanisms underlying the protective effects of NAC and other potential GPX4-reducing substrates against ferroptosis. Show less

Conditions that led to the synthesis of iron-sulfur clusters coordinated to tripeptides with a single thiolate ligand were investigated by UV-vis, NMR, EPR, and Mössbauer spectroscopies and by electrochemistry. Increasing concentrations of hydrosulfide correlated with the formation of higher nuclearity iron-sulfur clusters from mononuclear to [2Fe-2S] to [4Fe-4S] and finally to a putative, nitrogenase-like [6Fe-9S] complex. Increased nuclearity was also associated with decreased dynamics and increased stability. The synthesis of higher nuclearity iron-sulfur clusters is compatible with shallow, alkaline bodies of water on the surface of the early Earth, although other niche environments are possible. Because of the plasticity of such complexes, the type of iron-sulfur cluster formed on the prebiotic Earth would have been greatly influenced by the chemical environment and the thiolate containing scaffold. The discovery that all the major classes of iron-sulfur clusters easily form under prebiotically reasonable conditions broadens the chemistry accessible to protometabolic systems. Show less

Mitochondrial outer membrane permeabilization (MOMP) refers to the increase in permeability of the mitochondrial outer membrane, allowing proteins, DNA, and other molecules to pass through the intermembrane space into the cytosol. As a crucial event in the induction of apoptosis, MOMP plays a significant role in regulating various forms of cell death, including apoptosis, ferroptosis, and pyroptosis. Importantly, MOMP is not a binary process of "all-or-nothing." Under sub-lethal stress stimuli, cells may experience a phenomenon referred to as minority MOMP (miMOMP), where only a subset of mitochondria undergo functional impairment, thereby disrupting the normal life cycle of the cell. This can lead to pathological and physiological changes such as tumor formation, cellular senescence, innate immune dysfunction, and chronic inflammation. This review focuses on the diversity of MOMP events to elucidate how varying degrees of MOMP under different stress conditions influence cell fate. Additionally, it summarizes the current research progress on novel antitumor therapeutic strategies targeting MOMP in clinical contexts. Show less

Phospholipids containing a single polyunsaturated fatty acyl tail (PL-PUFA1s) are considered the driving force behind ferroptosis, whereas phospholipids with diacyl-PUFA tails (PL-PUFA2s) have been rarely characterized. Dietary lipids modulate ferroptosis, but the mechanisms governing lipid metabolism and ferroptosis sensitivity are not well understood. Our research revealed a significant accumulation of diacyl-PUFA phosphatidylcholines (PC-PUFA2s) following fatty acid or phospholipid treatments, correlating with cancer cell sensitivity to ferroptosis. Depletion of PC-PUFA2s occurred in aging and Huntington's disease brain tissue, linking it to ferroptosis. Notably, PC-PUFA2s interacted with the mitochondrial electron transport chain, generating reactive oxygen species (ROS) for initiating lipid peroxidation. Mitochondria-targeted antioxidants protected cells from PC-PUFA2-induced mitochondrial ROS (mtROS), lipid peroxidation, and cell death. These findings reveal a critical role for PC-PUFA2s in controlling mitochondria homeostasis and ferroptosis in various contexts and explain the ferroptosis-modulating mechanisms of free fatty acids. PC-PUFA2s may serve as diagnostic and therapeutic targets for modulating ferroptosis. Show less

Ferroptosis is a distinct form of necrotic cell death caused by overwhelming lipid peroxidation, and emerging evidence indicates a major contribution to organ damage in multiple pathologies. However, ferroptosis has not yet been visualized in vivo due to a lack of specific probes, which has severely limited the study of how the immune system interacts with ferroptotic cells and how this process contributes to inflammation. Consequently, whether ferroptosis has a physiological role has remained a key outstanding question. Here we identify a distinct, ferroptotic-like, necrotic cell death occurring in vivo during wounding of the Drosophila embryo using live imaging. We further demonstrate that macrophages rapidly engage these necrotic cells within the embryo but struggle to engulf them, leading to prolonged, frustrated phagocytosis and frequent corpse disintegration. Conversely, suppression of the ferroptotic programme during wounding delays macrophage recruitment to the injury site, pointing to conflicting roles for ferroptosis during inflammation in vivo. Show less

Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation that tumours exploit to counteract phospholipid oxidation1,2. Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation3, we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt's lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis. Show less

Title: Photoinduction of Ferroptosis and cGAS-STING Activation by a H Abstract: Triggering ferroptosis represents a promising anticancer therapeutic strategy, but the development of a selective ferroptosis inducer for cancer-specific therapy remains a great challenge. Herein, a H2S-responsive iridium(III) complex NA-Ir has been well-designed as a ferroptosis inducer. NA-Ir could selectively light up H2S-rich cancer cells, primarily localize in mitochondria, intercalate into mitochondrial DNA (mtDNA), and induce mtDNA damage, exhibiting higher anticancer activity under light irradiation. Mechanistic studies showed that NA-Ir-mediated PDT triggered lipid peroxidation and glutathione peroxidase 4 downregulation through ROS production and GSH depletion, resulting in ferroptosis through multiple pathways. Moreover, the intense mtDNA damage can activate the cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) pathway, leading to ferritinophagy and further ferroptosis. RNA-sequencing analysis showed that NA-Ir-mediated PDT mainly affects the expression of genes related to ferroptosis, autophagy, and cancer immunity. This study demonstrates the first cancer-specific example with ferroptosis and cGAS-STING activation, which provides a new strategy for multimodal synergistic therapy. Show less

Dihydroorotate dehydrogenase (DHODH)-mediated ferroptosis defense is a targetable vulnerability in cancer. Currently, only a few DHODH inhibitors have been utilized in clinical practice. To further enhance DHODH targeting, we introduced the mitochondrial targeting group triphenylphosphine (TPP) to brequinar (BRQ), a robust DHODH inhibitor, resulting in the creation of active molecule B2. This compound exhibits heightened anticancer activity, effectively inhibiting proliferation in various cancer cells, and restraining tumor growth in melanoma xenografts in mice. B2 achieves these effects by targeting DHODH, triggering the formation of reactive oxygen species (ROS), promoting mitochondrial lipid peroxidation, and inducing ferroptosis in B16F10 and A375 cells. Surprisingly, B2 significantly downregulates PD-L1 and alleviates immune suppression. Importantly, B2 exhibits no apparent adverse effects in mice. Collectively, these findings highlight that enhancing the mitochondrial targeting capability of the DHODH inhibitor is a promising therapeutic approach for melanoma treatment. Show less

Ferroptosis is a non-apoptotic form of cell death that can be triggered by inhibiting the system xc- cystine/glutamate antiporter or the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4). We have investigated how cell cycle arrest caused by stabilization of p53 or inhibition of cyclin-dependent kinase 4/6 (CDK4/6) impacts ferroptosis sensitivity. Here, we show that cell cycle arrest can enhance sensitivity to ferroptosis induced by covalent GPX4 inhibitors (GPX4i) but not system xc- inhibitors. Greater sensitivity to GPX4i is associated with increased levels of oxidizable polyunsaturated fatty acid-containing phospholipids (PUFA-PLs). Higher PUFA-PL abundance upon cell cycle arrest involves reduced expression of membrane-bound O-acyltransferase domain-containing 1 (MBOAT1) and epithelial membrane protein 2 (EMP2). A candidate orally bioavailable GPX4 inhibitor increases lipid peroxidation and shrinks tumor volumes when combined with a CDK4/6 inhibitor. Thus, cell cycle arrest may make certain cancer cells more susceptible to ferroptosis in vivo. Show less

Central to the quest of understanding the emergence of life is to uncover the role of metals, particularly iron, in shaping prebiotic chemistry. Iron, as the most abundant of the accessible transition metals on the prebiotic Earth, played a pivotal role in early biochemical processes and continues to be indispensable to modern biology. Here, we discuss our recent contributions to probing the plausibility of prebiotic complexes with iron, including heme and iron-sulfur clusters, in mediating chemistry beneficial to a protocell. Laboratory experiments and spectroscopic findings suggest plausible pathways, often facilitated by UV light, for the synthesis of heme and iron-sulfur clusters. Once formed, heme displays catalytic, peroxidase-like activity when complexed with amphiphiles. This activity could have been beneficial in two ways. First, heme could have catalytically removed a molecule (H₂O₂) that could have had degradative effects on a protocell. Second, heme could have helped in the synthesis of the building blocks of life by coupling the reduction of H₂O₂ with the oxidation of organic substrates. The necessity of amphiphiles to avoid the formation of inactive complexes of heme is telling, as the modern-day electron transport chain possesses heme embedded within a lipid membrane. Conversely, prebiotic iron-sulfur peptides have yet to be reported to partition into lipid membranes, nor have simple iron-sulfur peptides been found to be capable of participating in the synthesis of organic molecules. Instead, iron-sulfur peptides span a wide range of reduction potentials complementary to the reduction potentials of hemes. The reduction potential of iron-sulfur peptides can be tuned by the type of iron-sulfur cluster formed, e.g., [2Fe-2S] versus [4Fe-4S], or by the substitution of ligands to the metal center. Since iron-sulfur clusters easily form upon stochastic encounters between iron ions, hydrosulfide, and small organic molecules possessing a thiolate, including peptides, the likelihood of soluble iron-sulfur clusters seems to be high. What remains challenging to determine is if iron-sulfur peptides participated in early prebiotic chemistry or were recruited later when protocellular membranes evolved that were compatible with the exploitation of electron transfer for the storage of energy as a proton gradient. This problem mirrors in some ways the difficulty in deciphering the origins of metabolism as a whole. Chemistry that resembles some facets of extant metabolism must have transpired on the prebiotic Earth, but there are few clues as to how and when such chemistry was harnessed to support a (proto)cell. Ultimately, unraveling the roles of hemes and iron-sulfur clusters in prebiotic chemistry promises to deepen our understanding of the origins of life on Earth and aids the search for life elsewhere in the universe. Show less

Ferroptosis, spurred by excess labile iron and lipid peroxidation, is implicated in various diseases. Advances have been made in comprehending the lipid-peroxidation side of ferroptosis, but the exact role of iron in driving ferroptosis remains unknown. Although iron overload is characterized in multiple disease states, the potential role of ferroptosis within them remains undefined. This overview focuses on the 'ferro' side of ferroptosis, highlighting iron dysregulation in human diseases and potential therapeutic strategies targeting iron regulation and metabolism. Show less

Iron-sulfur (Fe-S) clusters are an essential and ubiquitous class of protein-bound prosthetic centers that are involved in a broad range of biological processes (e.g. respiration, photosynthesis, DNA replication and repair and gene regulation) performing a wide range of functions including electron transfer, enzyme catalysis, and sensing. In a general manner, Fe-S clusters can gain or lose electrons through redox reactions, and are highly sensitive to oxidation, notably by small molecules such as oxygen and nitric oxide. The [2Fe-2S] and [4Fe-4S] clusters, the most common Fe-S cofactors, are typically coordinated by four amino acid side chains from the protein, usually cysteine thiolates, but other residues (e.g. histidine, aspartic acid) can also be found. While diversity in cluster coordination ensures the functional variety of the Fe-S clusters, the lack of conserved motifs makes new Fe-S protein identification challenging especially when the Fe-S cluster is also shared between two proteins as observed in several dimeric transcriptional regulators and in the mitoribosome. Thanks to the recent development of in cellulo, in vitro, and in silico approaches, new Fe-S proteins are still regularly identified, highlighting the functional diversity of this class of proteins. In this review, we will present three main functions of the Fe-S clusters and explain the difficulties encountered to identify Fe-S proteins and methods that have been employed to overcome these issues. Show less

Ferroptosis, a form of regulated cell death mediated by lipid peroxidation (LPO), has become the subject of intense research due to its potential therapeutic applications in cancer chemotherapy as well as its pathophysiological role in ischemic organ injury. The role of mitochondrial lipid peroxidation (LPO) in ferroptosis remains poorly understood. We show that supplementation of exogenous iron in the form of ferric ammonium citrate (FAC) in combination with buthionine sulfoximine (BSO, an inhibitor of glutathione biosynthesis) induces mitochondrial lipid peroxidation that precedes ferroptosis in normal human fibroblasts. The mitochondrial-targeted antioxidant SkQ1 and the redox mediator methylene blue, which inhibits the production of reactive oxygen species (ROS) in complex I of the mitochondrial electron transport chain, prevent both mitochondrial lipid peroxidation and ferroptosis, but do not affect the cytosolic ROS accumulation. These data indicate that mitochondrial lipid peroxidation is required for ferroptosis induced by exogenous iron. FAC in the absence of BSO stimulates mitochondrial peroxidation without reducing cell viability. Glutathione depletion by BSO does not affect FAC-induced mitochondrial LPO but strongly stimulates the accumulation of ROS in the cytosol. These data allow us to conclude that mitochondrial LPO is not sufficient for ferroptosis and that cytosolic ROS mediates additional oxidative events that stimulate ferroptosis in conjunction with mitochondrial LPO. Show less

AbstractMitochondria, recognized as the cellular powerhouses, are indispensable organelles responsible for crucial cellular processes, such as energy metabolism, material synthesis, and signaling transduction. Their intricate involvement in a broad spectrum of diseases, particularly cancer, has propelled the exploration of mitochondria‐targeting treatment as a promising strategy for cancer therapy. Since the groundbreaking discovery of cisplatin, the trajectory of research on the development of metal complexes have been marked by continuous advancement, giving rise to a diverse array of metallodrugs characterized by variations in ligand types, metal center properties, and oxidation states. By specifically targeting mitochondria, these metallodrugs exhibit the remarkable ability to elicit various programmed cell death pathways, encompassing apoptosis, autophagy, and ferroptosis. This review primarily focuses on recent developments in transition metal‐based mitochondria‐targeting agents, offering a comprehensive exploration of their capacity to induce distinct cell death modes. The aim is not only to disseminate knowledge but also to stimulate an active field of research toward new clinical applications and novel anticancer mechanisms. Show less

ConspectusThe study of the origin of life requires a multifaceted approach to understanding where and how life arose on Earth. One of the most compelling hypotheses is the chemosynthetic origin of life at hydrothermal vents, as this condition has been considered viable for early forms of life. The continuous production of H2 and heat by serpentinization generates reductive conditions at hydrothermal vents, in which CO2 can be used to build large biomolecules. Although this involves surface catalysis and an autocatalytic process, in which solid minerals act as catalysts in the conversion of CO2 to metabolically important organic molecules, the systematic investigation of heterogeneous catalysis to comprehend prebiotic chemistry at hydrothermal vents has not been undertaken.In this Account, we discuss geochemical CO2 fixation to metabolic intermediates by synthetic minerals at hydrothermal vents from the perspective of heterogeneous catalysis. Ni and Fe are the most abundant transition metals at hydrothermal vents and occur in the active site of the enzymes carbon monoxide dehydrogenases/acetyl coenzyme A synthases (CODH/ACS). Synthetic free-standing NiFe alloy nanoparticles can convert CO2 to acetyl coenzyme A pathway intermediates such as formate, acetate, and pyruvate. The same alloy can further convert pyruvate to citramalate, which is essential in the biological citramalate pathway. Thermal treatment of Ni3Fe nanoparticles under NH3, which can occur in hydrothermal vents, results in Ni3FeN/Ni3Fe heterostructures. This catalyst has been demonstrated to produce prebiotic formamide and acetamide from CO2 and H2O using Ni3FeN/Ni3Fe as both substrate and catalyst. In the process of serpentinization, Co can be reduced in the vicinity of olivine, a Mg-Fe silicate mineral. This produces CoFe and CoFe2 with serpentine in nature, representing SiO2-supported CoFe alloys. In mimicking these natural minerals, synthetic SiO2-supported CoFe alloys demonstrate the same liquid products as NiFe alloys, namely, formate, acetate, and pyruvate under mild hydrothermal vent conditions. In contrast to the NiFe system, hydrocarbons up to C6 were detected in the gas phase, which is also present in hydrothermal vents. The addition of alkali and alkaline-earth metals to the catalysts results in enhanced formate concentration, playing a promotional role in CO2 reduction. Finally, Co was loaded onto ordered mesoporous SiO2 after modification with cations to simulate the minerals found in hydrothermal vents. These catalysts were then investigated under diminished H2O concentration, revealing the conversion of CO2 to CO, CH4, methanol, and acetate. Notably, the selectivity to metabolically relevant methanol was enhanced in the presence of cations that could generate and stabilize the methoxy intermediate. Calculation using the machine learning approach revealed the possibility of predicting the selectivity of CO2 fixation when modifying mesoporous SiO2 supports with heterocations. Our research demonstrates that minerals at hydrothermal vents can convert CO2 into metabolites under a variety of prebiotic conditions, potentially paving the way for modern biological CO2 fixation processes. Show less