Derivation of ecological safety thresholds and risk assessment of new SDHI fungicides in farmland system.

Succinate dehydrogenase inhibitor (SDHI) fungicides have become some of the top-selling fungicides in recent years. As the utilization of these fungicides intensifies, the corresponding potential risks to the environment proportionately increase. However, there is still limited knowledge about their toxic effects on ecosystems. In this study, acute toxicity data from laboratory assessments of the springtail Folsomia candida, alongside collected data from terrestrial and aquatic non-target species, were utilized to construct a species sensitivity distribution (SSD) model for both terrestrial and aquatic non-target organisms. Subsequently, we derived ecological baseline values for diverse scenarios within ecosystems. The results indicated that benzovindiflupyr exhibited the highest 7-day median lethal concentration (7d-LC50) to Folsomia candida at 2.0 µg cm-2, while the toxicity levels of other SDHI fungicides varied, ranging from 99 to 304 µg cm-2. In agricultural environments, the Hazard Concentration for 5 % of species (HC5) values for fluxapyroxad, boscalid, sedaxane, and isopyrazam were determined to be 8.0, 1240, 12.97, and 25.37 g ha-1, respectively. In aquatic environments, the HC5 values for benzovindiflupyr, fluxapyroxad, boscalid, sedaxane, isopyrazam, and carboxin were 0.0013, 0.022, 1.76, 0.372, 0.013, and 0.161 mg L-1, respectively. In an evaluation of typical agricultural scenarios within China, SDHI fungicides were found to exert substantial ecological risks to terrestrial non-target fauna and aquatic ecosystems around agricultural fields. Specifically, isopyrazam and fluxapyroxad were identified as posing heightened ecological risks to Typhlodromus pyri and Aphidius rhopalosiphi. Moreover, the application of benzovindiflupyr, carboxin, isopyrazam, and fluxapyroxad in paddy field environments is associated with unacceptable risks to groundwater. The findings of this study contribute significantly to the environmental risk evaluation of SDHI fungicides within farmland system, thereby informing the development of policy frameworks for their scientifically grounded application.

Succinate Dehydrogenase and Human Disease: Novel Insights into a Well-Known Enzyme.

Succinate dehydrogenase (also known as complex II) plays a dual role in respiration by catalyzing the oxidation of succinate to fumarate in the tricarboxylic acid (TCA) cycle and transferring electrons from succinate to ubiquinone in the mitochondrial electron transport chain (ETC). Owing to the privileged position of SDH/CII, its dysfunction leads to TCA cycle arrest and altered respiration. This review aims to elucidate the widely documented profound metabolic effects of SDH/CII deficiency, along with the newly unveiled survival mechanisms in SDH/CII-deficient cells. Such an understanding reveals exploitable vulnerabilities for strategic targeting, which is crucial for the development of novel and more precise therapies for primary mitochondrial diseases, as well as for familial and sporadic cancers associated with SDH/CII mutations.

Varied sensitivity to boscalid among different Clarireedia species causing dollar spot in turfgrass.

Dollar spot, a highly destructive turfgrasses disease worldwide, is caused by multiple species within the genus Clarireedia. Previous research indicated varying sensitivity to boscalid among Clarireedia populations not historically exposed to succinate dehydrogenase inhibitors (SDHIs). This study confirms that the differential sensitivity pattern is inherent among different Clarireedia spp., utilizing a combination of phylogenetic analyses, in vitro cross-resistance assays, and genetic transformation of target genes with different mutations. Furthermore, greenhouse inoculation experiments revealed that the differential boscalid sensitivity did not lead to pathogenicity issues or fitness penalties, thereby not resulting in control failure by boscalid. This research underscores the importance of continuous monitoring of fungicide sensitivity trends and highlights the complexity of chemical control of dollar spot due to the inherent variability in fungicide sensitivity among different Clarireedia spp.

The occurrence and mechanism of field resistance to boscalid and pyraclostrobin in Stemphylium solani, the causal agent of tomato gray leaf spot in China.

The destructive disease gray leaf spot, caused by Stemphylium solani, is prevalent in tomato plants in China. A variety of fungicides have been extensively used for controlling the disease, with a particular focus on succinate dehydrogenase inhibitors (SDHIs) and quinone outside inhibitors (QoIs). However, there was a lack of information regarding the resistance of S. solani to boscalid (SDHI) and pyraclostrobin (QoI) in China. In this study, the sensitivity of S. solani to boscalid and pyraclostrobin was monitored. The EC50 values for boscalid ranged from 0.02 to 3.0 µg∙mL-1, with an average value of 0.62 µg∙mL-1, while the EC50 values for pyraclostrobin ranged from 0.21 to 14.71 µg∙mL-1, with an average value of 6.03 µg∙mL-1. Based on these findings, the frequencies of observed resistance were as follows: 36.7% for boscalid and 50% for pyraclostrobin; while the resistance frequency to both boscalid and pyraclostrobin in S. solani was 19.4%. The mutation associated with boscalid resistance in S. solani within tomato fields was identified as SdhB-H277Y, while the mutation related to pyraclostrobin resistance was found in cytochrome b, specifically Cytb-G143A. The resistant mutants displayed diminished fitness in terms of mycelial growth, yet their pathogenicity exhibited no significant disparities. To delay the development of resistance, it is advisable to employ a rotation strategy using alternative fungicides with different modes of action or mix with fungicides with multi-site-contact activity for disease management.

Imaging finding of renal masses associated with pathogenic variation in succinate dehydrogenase subunit B gene.

PURPOSE: Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a newly defined, rare subtype of renal cancer, associated with pathogenic variations in the Succinate Dehydrogenase Subunit B (SDHB) gene. Our aim is to investigate the imaging findings of SDHB-associated renal tumors, utilizing cross-sectional and FDG-PET imaging in patients with pathogenic variations in SDHB gene, to facilitate accurate tumor characterization. METHODS: Twenty SDH-deficient tumors from 16 patients with pathogenic variations in SDHB gene were retrospectively evaluated using cross-sectional and FDG-PET imaging. Clinical findings such as demographics, family history, extra-renal findings and metastases were recorded. Tumor imaging characteristics on CT/MRI included were laterality, size, homogeneity, morphology, margins, internal content, T1/T2 signal intensity, enhancement features, and restricted diffusion. RESULTS: Sixteen patients (median age 31 years, IQR 19-41, 8 males) were identified with 68.8 % of patients having a known family history of SDHB variation. 81.3 % of lesions were solitary and majority were solid (86.7 % on CT, 87.5 % on MRI) with well-defined margins in >62.5 % of lesions, without evidence of internal fat, calcifications, or vascular invasion. 100 % of lesions demonstrated restricted diffusion and avid enhancement, with degree >75 % for most lesions on CT and MRI. On FDG-PET, all renal masses showed increased radiotracer uptake. 43.8 % of patients demonstrated extra-renal manifestations and 43.8 % had distant metastasis. CONCLUSION: SDHB-associated RCC is predominantly noted in young patients with no gender predilection. On imaging, SDH-deficient RCC are frequently unilateral, solitary, and solid with well-defined margins demonstrating avid enhancement with variability in enhancement pattern and showing restricted diffusion.

Overview of recent guidelines and consensus statements on initial screening and management of phaeochromocytoma and paraganglioma in SDHx pathogenic variant carriers and patients.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours with a strong genetic predisposition, involving over 20 genes and with germline pathogenic variants identified in 40 % of cases. The succinate dehydrogenase (SDHx) genes are the most commonly implicated in hereditary PPGLs, accounting for 20 % of cases, and present unique diagnostic and treatment challenges due to their potential for multiple, recurrent, and aggressive manifestations, often necessitating lifelong follow-up. Over the past two decades, advances in biochemical and imaging assessments, management, and follow-up protocols have significantly improved care for both adult and paediatric patients. These advances include next-generation sequencing, new biochemical tests, cluster-specific functional imaging, and improved surgical and radiotherapy techniques, such as stereotactic surgery and peptide receptor radionuclide therapy (PRRT). International consensus guidelines have been developed to standardise the management of patients with SDHx pathogenic variants, emphasising multidisciplinary approaches and frequent tumour board discussions. These guidelines, summarised below, cover recommendations for initial genetic testing, tumour screening, follow-up care, and management of patients and asymptomatic carriers.

Insights into the developmental and cardiovascular toxicity of bixafen using zebrafish embryos and larvae.

Bixafen (BIX), a member of the succinate dehydrogenase inhibitor (SDHI) class of fungicides, has seen a surge in interest due to its expanding market presence and positive development outlook. However, there is a growing concern about its potential harm to aquatic life, largely due to its resistance to breaking down in the environment. In this study, we thoroughly examined the toxicological impact of BIX on zebrafish as a model organism. Our results revealed that BIX significantly hindered the development of zebrafish embryos, leading to increased mortality, hatching failures, and oxidative stress. Additionally, we observed cardiovascular abnormalities, including dilated cardiac chambers, reduced heart rate, sluggish blood circulation, and impaired vascular function. Notably, BIX also altered the expression of key genes involved in cardiovascular development, such as myl7, vmhc, nkx2.5, tbx5, and flt1. In summary, BIX was found to induce developmental and cardiovascular toxicity in zebrafish, underscoring the risks associated with SDHI pesticides and emphasizing the need for a reassessment of their impact on human health. These findings are crucial for the responsible use of BIX.

Design, synthesis and structure-activity relationship of novel pyrazole-4-carboxamide derivatives.

BACKGROUND: Plant diseases seriously decrease the yield and quality of agricultural crops. Fungicide treatments remain the main means of field fungi control. However, the residual activity of fungicides is rapidly reduced due to various factors in the natural environment, therefore the development of agents with novel modes of action is desirable. It is highly required to design and develop new fungicides to address the resistance issue. Designing low impact chemicals to safely and sustainably address needs of agriculture. RESULTS: In this work, we used the highly active fluxapyroxad and flutolanil as parent structures, to design and synthesize a series of pyrazole-4-carboxamide derivatives. Some of the pyrazole-4-carboxamide derivatives exhibit fungicidal activities that are comparable to or higher than those of the commercialized fungicides fluxapyroxad and bixafen. In particular, compounds TM-1, TM-2, TM-3, TM-4, TM-5, TM-7 and TM-8 showed excellent fungicidal activities against corn rust that were 2-4 times higher than those of fluxapyroxad and bixafen. Field trial results demonstrated that at the same dosage levels, compound TM-2 exhibited comparable field control efficacy against wheat rust as compared to triadimefon and pyrazophenamide. Molecular docking simulations reveal that compound TM-2 interacts with TRP 173 of succinate dehydrogenase (SDH) through hydrogen bonding, which could explain the probable mechanism of action between compound TM-2 and the target protein. CONCLUSION: These results indicate that compound TM-2 may be a promising fungicide candidate and provide valuable reference for further investigation. © 2024 Society of Chemical Industry.

SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies.

Succinate dehydrogenase (SDH) plays pivotal roles in maintaining cellular metabolism, modulating regulatory control over both the tricarboxylic acid cycle and oxidative phosphorylation to facilitate energy production within mitochondria. Given that SDH malfunction may serve as a hallmark triggering pseudo-hypoxia signaling and promoting tumorigenesis, elucidating the impact of SDH assembly defects on mitochondrial functions and cellular responses is of paramount importance. In this study, we aim to clarify the role of SDHAF2, one assembly factor of SDH, in mitochondrial respiratory activities. To achieve this, we utilize the CRISPR/Cas9 system to generate SDHAF2 knockout in HeLa cells and examine mitochondrial respiratory functions. Our findings demonstrate a substantial reduction in oxygen consumption rate in SDHAF2 knockout cells, akin to cells with inhibited SDH activity. In addition, in our in-gel activity assays reveal a significant decrease not only in SDH activity but also in cytochrome c oxidase (COX) activity in SDHAF2 knockout cells. The reduced COX activity is attributed to the assembly defect and remains independent of SDH inactivation or SDH complex disassembly. Together, our results indicate a critical role of SDHAF2 in regulating respiration by facilitating the assembly of COX.

Identification of Chemical Scaffolds That Inhibit the Mycobacterium tuberculosis Respiratory Complex Succinate Dehydrogenase.

Drug-resistant Mycobacterium tuberculosis is a significant cause of infectious disease morbidity and mortality for which new antimicrobials are urgently needed. Inhibitors of mycobacterial respiratory energy metabolism have emerged as promising next-generation antimicrobials, but a number of targets remain unexplored. Succinate dehydrogenase (SDH), a focal point in mycobacterial central carbon metabolism and respiratory energy production, is required for growth and survival in M. tuberculosis under a number of conditions, highlighting the potential of inhibitors targeting mycobacterial SDH enzymes. To advance SDH as a novel drug target in M. tuberculosis, we utilized a combination of biochemical screening and in-silico deep learning technologies to identify multiple chemical scaffolds capable of inhibiting mycobacterial SDH activity. Antimicrobial susceptibility assays show that lead inhibitors are bacteriostatic agents with activity against wild-type and drug-resistant strains of M. tuberculosis. Mode of action studies on lead compounds demonstrate that the specific inhibition of SDH activity dysregulates mycobacterial metabolism and respiration and results in the secretion of intracellular succinate. Interaction assays demonstrate that the chemical inhibition of SDH activity potentiates the activity of other bioenergetic inhibitors and prevents the emergence of resistance to a variety of drugs. Overall, this study shows that SDH inhibitors are promising next-generation antimicrobials against M. tuberculosis.

[The role of mitochondrial dysfunction in the stabilization of the glaucomatous process]. / Znachenie mitokhondrial'noi disfunktsii v stabilizatsii glaukomnogo protsessa.

Many key aspects of retinal ganglion cell (RGC) neurodegeneration in glaucoma are associated with mitochondrial dysfunction. Understanding the mechanisms and relationships between structural and functional changes in mitochondria would be beneficial for developing mitochondria-targeted therapeutic strategies to protect RGCs from glaucomatous neurodegeneration. PURPOSE: This study determines the extent of mitochondrial dysfunction in patients with primary open-angle glaucoma (POAG) and evaluates the potential for stabilizing the glaucomatous process by improving mitochondrial functional activity and energy production by therapy with Mexidol and Mexidol FORTE 250. MATERIAL AND METHODS: The study included 80 patients with moderate POAG with compensated intraocular pressure and 20 healthy volunteers. The extent of mitochondrial dysfunction was assessed by measuring the activity levels of mitochondrial enzymes: succinate dehydrogenase (SDH) and α-glycerophosphate dehydrogenase (α-GPDH) in peripheral blood lymphocytes using cytochemical analysis and cytometric morphology and density analysis (cytomorphodensitometry). Patients in the main group received sequential therapy with Mexidol as follows: Mexidol solution for intravenous and intramuscular administration at 50 mg/ml, 300 mg daily intramuscularly for 14 days, followed by Mexidol FORTE 250 tablets, one tablet three times daily for 56 days. Stabilization of glaucomatous optic neuropathy during treatment was evaluated using a comprehensive set of perimetric, electrophysiological, and structural-topographical methods at 14, 56, and 90 days. RESULTS: Sequential therapy in the main group resulted in a significant increase in mitochondrial enzyme activity at 14 and 56 days compared to baseline, with a gradual regression by the end of the observation period (90 days). This was accompanied by an increase in the number of mitochondria and an increase in their optical density as measured by cytomorphodensitometry. The improvement in mitochondrial enzyme activity at 14 and 56 days was associated with positive changes in the structural and functional parameters of the retina, as evidenced by static perimetry, optical coherence tomography, and a series of electrophysiological tests. CONCLUSION: The obtained data can be used to optimize POAG therapy by reducing mitochondrial dysfunction and stabilizing glaucomatous optic neuropathy.

Management and follow-up strategies for patients with head and neck paraganglioma.

OBJECTIVE: Head-neck paragangliomas (HNPGLs) are rare tumors with approximately half arising due to germline pathogenic variants (PVs) in succinate dehydrogenase genes (SDHx). Patients with HNPGL have heterogeneous propensity to recur and metastasize. Thus, we aim to assess prevalence and predictors of recurrent (RD) and/or metastatic disease in patients with and without SDHx-related HNPGLs. DESIGN AND METHODS: This cross-sectional study used retrospective data of 214 patients enrolled in six referral centers. Data included sex, age, primary tumor treatment, location, and size, biochemical phenotype, germline PVs, presence of RD (locoregional or new tumor), and/or metastasis. RESULTS: Patients with and without SDHx-related HNPGLs showed 74% and 40% prevalence of RD, respectively. Patients without SDHx-related HNPGLs presented with recurrent tumors only in head-neck regions. The only independent predictor for RD in the entire cohort was presence of SDHx PVs. Metastatic prevalence reached 9%-13%. For patients with SDHx-related HNPGLs, large tumor size (>2.3 cm, OR:50.0, CI:2.6-977.6), young age at initial diagnosis (<42years, OR:27.3, CI:1.8-407.2), and presence of SDHB PV (OR:15.6; CI:1.5-164.8) were independent predictors of metastasis. For patients without SDHx-related HNPGLs, only carotid-body location was an independent predictor of metastasis (OR:18.9, CI:2.0-182.5). CONCLUSIONS: Patients without SDHx-related HNPGLs require long-term follow-up due to high prevalence of RD with imaging largely restricted to head-neck regions. As carotid-body HNPGLs have the highest metastatic risk among sporadic tumors, radical treatment with frequent follow-up is suggested until population-based data are available. Importantly, patients with SDHx-related HNPGLs might benefit from early radical treatment when tumors are still small to reduce metastatic risk.

Identification of Succinate Dehydrogenase Gene Variant Carriers by Blood Biomarkers.

Background: Carriers of germline pathogenic variants (PVs) in succinate dehydrogenase genes (SDHx) are at risk of developing tumors, including paragangliomas, gastrointestinal stromal tumors, and renal cell carcinomas. Early tumor detection is paramount for improved clinical outcome. Blood-based biomarkers could aid in identifying individuals with PVs early and provide functional evidence in patients with variants of unknown significance. Methods: Blood plasma, urine, peripheral blood mononuclear cells, and erythrocytes from patients with and without SDHx PVs were investigated for central carbon metabolites. These were measured by liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance spectroscopy and included among others, succinate, fumarate, α-ketoglutarate, and lactate. Results: Plasma succinate to fumarate ratios effectively distinguished tumor-bearing and asymptomatic patients with and without SDHx PV with promising diagnostic performance (areas under the receiver operating characteristic curve 0.86-0.95), although higher levels were noted in individuals with SDHB PV. Metabolites in urine and in peripheral blood mononuclear cell extracts were largely similar between groups. Erythrocytes showed strong metabolic alterations in patients with SDHx PV compared to controls, with 8 of 13 low-molecular organic acids being significantly different (P < .05). The lactate-α-ketoglutarate-ratio of erythrocytes identified individuals with SDHx PV equally well as plasma, with a sensitivity and specificity of 92% (AUC 0.97). Conclusion: Blood biomarkers have been underutilized for identifying carriers of SDHx PV or to validate variants of unknown significance. Our findings advocate for further investigation into a combined approach involving plasma and erythrocytes for future diagnostic strategies.

SDH-related head and neck paragangliomas: Unraveling PET radiomics beyond 18F-FDG.

Radiomics revolutionizes medical imaging by providing quantitative analysis that complements traditional qualitative assessments through advanced computational techniques. In this narrative review we have investigated the impact of succinate dehydrogenase (SDH) pathogenic variants on the radiomic profile of 18F-FDG, 18F-DOPA, and 68Ga-DOTA-peptides PET in paragangliomas, focusing on head and neck localizations (HNPGLs). This influence manifests in uptake intensity and textural heterogeneity, revealing a complex radiomic landscape that may reflect specific tumor behaviors and mutation statuses. By combining radiomic analysis with genetic data, we will gain new insights into the relationship between PET imaging features and underlying molecular changes. In the future, we envision an approach integrating macroscopic indices, such as lesion location, size, and SUV, with advanced computer-based algorithms. This comprehensive analysis could facilitate in vivo predictions of SDH pathogenic variants, thereby encouraging genetic testing, and ultimately improving patient outcomes.

A newly identified algicidal bacterium of Pseudomonas fragi YB2: Algicidal compounds and effects.

Harmful algal bloom (HAB) is an unresolved existing problem worldwide. Here, we reported a novel algicidal bacterium, Pseudomonas fragi YB2, capable of lysing multiple algal species. To Chlorella vulgaris, YB2 exhibited a maximum algicidal rate of 95.02 % at 120 h. The uniqueness of YB2 lies in its ability to self-produce three algicidal compounds: 2-methyl-1, 3-cyclohexanedione (2-MECHD), N-phenyl-2-naphthylamine, and cyclo (Pro-Leu). The algicidal properties of 2-MECHD have not been previously reported. YB2 significantly affected the chloroplast and mitochondrion, thus decreasing in chlorophyll a by 4.74 times for 120 h and succinate dehydrogenase activity by 103 times for 36 h. These physiological damages disrupted reactive oxygen species and Ca2+ homeostasis at the cellular level, increasing cytosolic superoxide dismutase (23 %), catalase (35 %), and Ca2+ influx. Additionally, the disruption of Ca2+ homeostasis rarely reported in algicidal bacteria-algae interaction was observed using the non-invasive micro-test technology. We proposed a putative algicidal mechanism based on the algicidal outcomes and physiological algicidal effects and explored the potential of YB2 through an algicidal simulation test. Overall, this study is the first to report the algicidal bacterium P. fragi and identify a novel algicidal compound, 2-MECHD, providing new insights and a potent microbial resource for the biocontrol of HAB.

Tricarboxylic Acid Cycle Relationships with Non-Metabolic Processes: A Short Story with DNA Repair and Its Consequences on Cancer Therapy Resistance.

Metabolic changes involving the tricarboxylic acid (TCA) cycle have been linked to different non-metabolic cell processes. Among them, apart from cancer and immunity, emerges the DNA damage response (DDR) and specifically DNA damage repair. The oncometabolites succinate, fumarate and 2-hydroxyglutarate (2HG) increase reactive oxygen species levels and create pseudohypoxia conditions that induce DNA damage and/or inhibit DNA repair. Additionally, by influencing DDR modulation, they establish direct relationships with DNA repair on at least four different pathways. The AlkB pathway deals with the removal of N-alkylation DNA and RNA damage that is inhibited by fumarate and 2HG. The MGMT pathway acts in the removal of O-alkylation DNA damage, and it is inhibited by the silencing of the MGMT gene promoter by 2HG and succinate. The other two pathways deal with the repair of double-strand breaks (DSBs) but with opposite effects: the FH pathway, which uses fumarate to help with the repair of this damage, and the chromatin remodeling pathway, in which oncometabolites inhibit its repair by impairing the homologous recombination repair (HRR) system. Since oncometabolites inhibit DNA repair, their removal from tumor cells will not always generate a positive response in cancer therapy. In fact, their presence contributes to longer survival and/or sensitization against tumor therapy in some cancer patients.

Advances in Molecular Mechanisms of Kidney Disease: Integrating Renal Tumorigenesis of Hereditary Cancer Syndrome.

Renal cell carcinoma (RCC) comprises various histologically distinct subtypes, each characterized by specific genetic alterations, necessitating individualized management and treatment strategies for each subtype. An exhaustive search of the PubMed database was conducted without any filters or restrictions. Inclusion criteria encompassed original English articles focusing on molecular mechanisms of kidney cancer. On the other hand, all non-original articles and articles published in any language other than English were excluded. Hereditary kidney cancer represents 5-8% of all kidney cancer cases and is associated with syndromes such as von Hippel-Lindau syndrome, Birt-Hogg-Dubè syndrome, succinate dehydrogenase-deficient renal cell cancer syndrome, tuberous sclerosis complex, hereditary papillary renal cell carcinoma, fumarate hydratase deficiency syndrome, BAP1 tumor predisposition syndrome, and other uncommon hereditary cancer syndromes. These conditions are characterized by distinct genetic mutations and related extra-renal symptoms. The majority of renal cell carcinoma predispositions stem from loss-of-function mutations in tumor suppressor genes. These mutations promote malignant advancement through the somatic inactivation of the remaining allele. This review aims to elucidate the main molecular mechanisms underlying the pathophysiology of major syndromes associated with renal cell carcinoma. By providing a comprehensive overview, it aims to facilitate early diagnosis and to highlight the principal therapeutic options available.

Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.

To examine the roles of mitochondrial calcium Ca2+ ([Ca2+]mt) and cytosolic Ca2+ ([Ca2+]cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced [Ca2+]mt and increased [Ca2+]cyt content. Despite decreased [Ca2+]mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of [14C16]palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that [Ca2+]cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from [Ca2+]mt and reveal a key role for [Ca2+]cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.

Metabolomic profiling of pheochromocytomas in dogs: Catecholamine phenotype and tricarboxylic acid cycle metabolites.

BACKGROUND: In humans with pheochromocytomas (PCCs), targeted metabolomics is used to determine the catecholamine phenotype or to uncover underlying pathogenic variants in tricarboxylic acid (TCA) cycle genes such as succinate dehydrogenase subunits (SDHx). HYPOTHESIS/OBJECTIVES: To analyze catecholamine contents and TCA cycle metabolites of PCCs and normal adrenals (NAs). ANIMALS: Ten healthy dogs, 21 dogs with PCC. METHODS: Prospective observational study. Dogs diagnosed with PCC based on histopathological and immunohistochemical confirmation were included. Tissue catecholamine contents and TCA metabolites in PCCs and NAs were measured by liquid chromatography with mass spectrometry or electrochemical detection. RESULTS: Compared to NAs, PCCs had significantly higher tissue proportion of norepinephrine (88% [median: range, 38%-98%] vs 14% [11%-26%]; P < .001), and significantly lower tissue proportion of epinephrine (12% [1%-62%] vs 86% [74%-89%]; P < .001). Pheochromocytomas exhibited significantly lower fumarate (0.4-fold; P < .001), and malate (0.5-fold; P = .008) contents than NAs. Citrate was significantly higher in PCCs than in NAs (1.6-fold; P = .015). One dog in the PCC group had an aberrant succinate : fumarate ratio that was 25-fold higher than in the other PCCs, suggesting an SDHx mutation. CONCLUSIONS AND CLINICAL IMPORTANCE: This study reveals a distinct catecholamine content and TCA cycle metabolite profile in PCCs. Metabolite profiling might be used to uncover underlying pathogenic variants in TCA cycle genes in dogs.

SDHA-related phaeochromocytoma and paraganglioma: review and clinical management.

Phaeochromocytomas and paragangliomas (collectively termed PPGL) are rare yet highly heritable neuroendocrine tumours, with over one-third of cases associated with germline pathogenic variants (PVs) in numerous genes. PVs in the succinate dehydrogenase subunit-A gene (SDHA) were initially implicated in hereditary PPGL in 2010, and SDHA has since become an important susceptibility gene accounting for up to 2.8% of cases. However, it remains poorly understood, particularly regarding the clinical nature of SDHA PPGL, rates of recurrence and metastasis, and the nature of metastatic disease. We present a narrative review of SDHA-related PPGL, covering pathophysiology, relevance to current clinical practice, and considerations for clinical genetics. We analyse a pool of 107 previously reported cases of SDHA-associated PPGL to highlight the spectrum of SDHA-related PPGL. Our analysis demonstrates that SDHA PPGL occurs across a wide age range (11-81 years) and affects men and women equally. SDHA PPGL typically presents as single tumours (91%), usually occurring in the head and neck (46%) or abdomen (43%, including 15% with phaeochromocytomas). Metastatic disease was reported in 25.5% of cases, with bone (82%) and lymph nodes (71%) being the most common sites of metastasis, often identified many years after the initial diagnosis. A family history of SDHA-related neoplasia was rare, reported in only 4% of cases. Understanding the clinical nature and risks associated with SDHA PVs is essential for facilitating the optimal management of patients and their families.