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Succinate dehydrogenase (SDH) is a key fungicidal target, but rational inhibitors design has been impeded by the lack of fungal SDH structure. Here, we show the cryo-EM structure of SDH from Saccharomyces cerevisiae ( Sc SDH) in apo (3.36 Å) and ubiquinone-1-bound (3.25 Å) states, revealing subunits architecture and quinone-binding sites (Q p ). Sc SDH is classified as a heme-deficient type-D SDH, utilizing conserved redox centers (FAD, [2Fe-2S], [4Fe-4S] and [3Fe-4S] clusters) for electron transfer. A 3.23 Å structure with pydiflumetofen (PYD) identified critical interactions, including hydrogen bonds with Trp_SDHB194 and Tyr_SDHD120, and a cation-π interaction with Arg_SDHC97. Leveraging this, we designed a SDH inhibitor E8 (enprocymid), exhibiting significant fungicidal activity ( K i  = 0.019 μM) and reduced zebrafish toxicity (LC 50 (96 h) = 1.01 mg a.i./L). This study elucidates the structure of fungal SDH and demonstrates the potential of Sc SDH for rational design of next-generation fungicides, addressing fungal resistance and environmental toxicity in agriculture. Fungal diseases threaten crops worldwide. By resolving the cryo-EM structure of fungal succinate dehydrogenase, researchers designed an inhibitor with broad antifungal activity, strong field performance, and reduced environmental toxicity.

Succinate dehydrogenase (SDH) also known as complex II or succinate:quinone oxidoreductase is an enzyme involved in both oxidative phosphorylation and tricarboxylic acid cycle; the processes that generate energy. SDH is a multi-subunit enzyme which requires a series of proteins for its proper assembly at several steps. This enzyme has medical significance as there is a broad range of human diseases from cancers to neurodegeneration related to SDH malfunction. Some of these disorders have recently been linked to defective assembly factors, reinvigorating further research in this area. Apart from that this enzyme has agricultural importance as many fungicides have been/will be designed targeting specifically this enzyme in plant fungal pathogens. In addition, we speculate it might be possible to design novel fungicides specifically targeting fungal assembly factors. Considering the medical and agricultural implications of SDH, the aim of this review is an overview of the SDH assembly factors and critical analysis of controversial issues around them.

Epigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood 1 – 3 . A subset of gastrointestinal stromal tumours (GISTs) lack canonical kinase mutations but instead have succinate dehydrogenase (SDH) deficiency and global DNA hyper-methylation 4 , 5 . Here, we associate this hyper-methylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, we mapped DNA methylation, CTCF insulators, enhancers, and chromosome topology in KIT -mutant, PDGFRA -mutant and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on a disrupted insulator that normally partitions a core GIST super-enhancer from the FGF4 oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary between enhancer and oncogene, and strongly upregulated FGF4 expression. We also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. Finally, we established a patient-derived xenograft (PDX) from an SDH-deficient GIST that faithfully maintains the epigenetics of the parental tumour, including hypermethylation and insulator defects. This PDX model is highly sensitive to FGF receptor (FGFR) inhibition, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions. Our study reveals how epigenetic alterations can drive oncogenic programs in the absence of canonical kinase mutations, with implications for mechanistic targeting of aberrant pathways in cancers. Gastrointestinal stromal tumours can be initiated by gain-of-function mutations of the KIT or PDGFRA oncogenes but also by loss of the metabolic complex succinate dehydrogenase (SDH), which leads to DNA hypermethylation; this study shows that in SDH-deficient tumours, displacement of CTCF insulators by DNA methylation activates oncogene expression, illustrating how epigenetic alterations can drive oncogenic signalling in the absence of kinase mutations.

Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring 1 marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite 2 . Itaconate and its membrane-permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines 2 , including IL-6 and IL-12 but not TNF. The major effects of itaconate on cellular metabolism during macrophage activation have been attributed to the inhibition of succinate dehydrogenase 2 , 3 , yet this inhibition alone is not sufficient to account for the pronounced immunoregulatory effects observed in the case of DI. Furthermore, the regulatory pathway responsible for such selective effects of itaconate and DI on the inflammatory program has not been defined. Here we show that itaconate and DI induce electrophilic stress, react with glutathione and subsequently induce both Nrf2 (also known as NFE2L2)-dependent and -independent responses. We find that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to toll-like receptor stimulation via inhibition of IκBζ protein induction. The regulation of IκBζ is independent of Nrf2, and we identify ATF3 as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of DI can ameliorate IL-17–IκBζ-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway. Our results demonstrate that targeting the DI–IκBζ regulatory axis could be an important new strategy for the treatment of IL-17–IκBζ-mediated autoimmune diseases. The immunoregulatory metabolite itaconate and its dimethyl derivative induce electrophilic stress and react with glutathione to induce both Nrf2-dependent and Nrf2-independent responses, resulting in AF3-mediated inhibition of the inflammation-related protein IκBζ.

Available cholinergic drugs for treating Alzheimer's disease (AD) provide modest symptomatic benefit. We hypothesized that co-administration of a peripheral anticholinergic to reduce dose-limiting adverse effects (AEs) would enable the safe/tolerable use of higher cholinesterase inhibitor doses and thus improve their antidementia efficacy. A modified single-blind, ascending-dose, phase IIa study of donepezil plus solifenacin (CPC-201) lasting 26 weeks was conducted in 41 patients with probable AD of moderate severity. Entry criteria included the use of donepezil at a dose of 10 mg/day during the preceding 3 months. The primary outcome measure was the maximum tolerated dose (MTD) of donepezil achieved (to protocol limit of 40 mg/day) when administered with the anticholinergic solifenacin 15 mg/day. Secondary measures included assessments of cognitive and global function, as well as of AEs. The mean ± SD donepezil MTD increased to 38 ± 0.74 mg/day (median 40 mg/day; p < 0.001); 88% of the study population safely attained this dose at the end of titration. Markedly reduced donepezil AE frequency, especially gastrointestinal, allowed this dose increase. There were no drug-related serious AEs or clinically significant laboratory abnormalities. At 26 weeks, Alzheimer's Disease Assessment Scale Cognitive Component scores in the efficacy evaluable population improved by 0.35 ± 0.85 points over baseline (p < 0.05), an estimated 2.5 ± 0.84 points above 10 mg/day donepezil and 5.4 ± 0.84 points above historic placebo (both p < 0.05). Clinical Global Impression of Improvement scores improved by 0.94 ± 0.20 to 3.1 ± 0.20 points (p < 0.001). The findings suggest that limiting donepezil AEs by co-administration of solifenacin allows the safe administration of substantially higher cholinesterase inhibitors doses that may augment cognitive and global benefits in patients with AD.

Succinate dehydrogenase (SDH), considered as the linkage between tricarboxylic acid cycle (TCA cycle) and electron transport chain, plays a vital role in adenosine triphosphate (ATP) production and cell physiology. SDH deficiency is a notable characteristic in many cancers. Recent studies have pinpointed the dysregulation of SDH can directly result its decreased catalytic activity and the accumulation of oncometabolite succinate, promoting tumor progression in different perspectives. This article expounds the various types of SDH deficiency in tumors and the corresponding pathological features. In addition, we discuss the mechanisms through which defective SDH fosters carcinogenesis, pioneering a categorization of these mechanisms as being either succinate-dependent or independent. Since SDH-deficient and cumulative succinate are regarded as the typical features of some cancers, like gastrointestinal stromal tumors, pheochromocytomas and paragangliomas, we summarize the presented medical management of SDH-deficient tumor patients in clinical and preclinical, identifying the potential strategies for future cancer therapeutics. Graphical abstract

Overactive bladder (OAB) is often treated with medications that block the cholinergic receptors in the bladder (known as anticholinergics). The effect of this medication class on cognition and risk of dementia has been increasingly studied over the past 40 years after initial studies suggested that the anticholinergic medication class could affect memory. Short-term randomized clinical trials demonstrated that the administration of the anticholinergic oxybutynin leads to impaired memory and attention, and large, population-based studies showed associations between several different anticholinergic medications and dementia. However, trials involving anticholinergics other than oxybutynin have not shown such substantial effects on short-term cognitive function. This discordance in results between short-term cognitive safety of OAB anticholinergics and the long-term increased dementia risk could be explained by the high proportion of patients using oxybutynin in the OAB subgroups of the dementia studies, or a study duration that was too short in the prospective clinical trials on cognition with other OAB anticholinergics. Notably, all studies must be interpreted in the context of potential confounding factors, such as when prodromal urinary symptoms associated with the early stages of dementia lead to an increase in OAB medication use, rather than the use of OAB medication causing dementia. In patients with potential risk factors for cognitive impairment, the cautious use of selected OAB anticholinergic agents with favourable physicochemical and pharmacokinetic properties and clinical trial evidence of cognitive safety might be appropriate.Anticholinergics are a common class of medication used in the treatment of overactive bladder. However, concerns have been raised over the potential association of anticholinergics and cognitive impairment or dementia. This Review discusses the clinical evidence and provides guidance for prescribing anticholinergics in at-risk populations.

Reactive oxygen species (ROS) are signaling molecules that regulate plant development and responses to stresses. Mitochondria are the source of most ROS in heterotrophic cells, and mitochondrial complex I and complex III are regarded as the main sites of ROS production in plant mitochondria. Recent studies have demonstrated that succinate dehydrogenase (SDH) also contributes to mitochondrial ROS production. However, the ability of SDH to generate ROS in plants is unclear. The aim of this study was to evaluate the role of SDH in mitochondrial ROS production. Our results demonstrated that SDH is a direct source of ROS in Arabidopsis thaliana and Oryza sativa, and the induction of ROS production by specific SDH inhibitors impaired plant growth. In addition, this effect was accompanied by the down-regulation of cell cycle genes and the up-regulation of stress-related genes. However, the partial inhibition of SDH by a competitive inhibitor decreased ROS production, which was associated with increased shoot and root growth, and prevented the down-regulation of cell cycle genes and the induction of stress-related genes by noncompetitive inhibitors. In conclusion, SDH plays an important role in ROS production, being a direct source of ROS in plant mitochondria and regulating plant development and stress responses.

Background Diabetic foot ulcers (DFU) typically exhibit impaired healing due to dysregulated re-epithelialization and excessive inflammation. Succinate, a key metabolic intermediate, is now understood to regulate inflammation through G Protein-Coupled Receptor 91 (GPR91) and succinate dehydrogenase (SDH), although its role in DFU remains unclear. Methods Co-cultures of M2 macrophages and epithelial cells, along with clinical samples, were used to analyze the expression of GPR91 and SDH. Functional assays were performed using high glucose (HG)-treated M2 macrophages (HG-M2) and an in vivo model. Cytokine and growth factor levels in cell supernatant were measured, and molecular mechanisms were explored via qRT-PCR, flow cytometry, and western blot analysis. Results Elevated glucose concentrations increased succinate levels and disrupted M2 macrophage–epidermal stem cells (EpSCs) interactions. GPR91 knockdown worsened HG-M2 dysfunction, while GPR91 overexpression (OE-GPR91) enhanced anti-inflammatory responses and reduced succinate. OE-GPR91-conditioned medium preserved EpSCs stemness and promoted migration mediated by hepatocyte growth factor (HGF). SDH inhibition (via Dimethyl malonate, DMM) boosted M2 macrophage activity by reducing reactive oxygen species (ROS) and upregulating Gpr91 expression. Mechanistically, GPR91 activated the pAkt/pGSK3β/β-catenin pathway, while DMM enhanced M2 macrophage function via the PI3K-Akt/pERK1/2 pathway. Conclusions GPR91 upregulation and SDH inhibition improve HG-M2 macrophage function, reduce inflammation, and enhance HGF-mediated EpSCs repair. Targeting both pathways may represent a promising approach to promote DFU healing. Graphical Abstract

When tissues are under physiological stresses, such as vigorous exercise and cold exposure, skeletal muscle cells secrete succinate into the extracellular space for adaptation and survival. By contrast, environmental toxins and injurious agents induce cellular secretion of succinate to damage tissues, trigger inflammation, and induce tissue fibrosis. Extracellular succinate induces cellular changes and tissue adaptation or damage by ligating cell surface succinate receptor-1 (SUCNR-1) and activating downstream signaling pathways and transcriptional programs. Since SUCNR-1 mediates not only pathological processes but also physiological functions, targeting it for drug development is hampered by incomplete knowledge about the characteristics of its physiological vs. pathological actions. This review summarizes the current status of extracellular succinate in health and disease and discusses the underlying mechanisms and therapeutic implications.