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Archives of Pathology & Laboratory... May 2020Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) is a subset of wild-type GIST that constitutes approximately 10% of gastric GISTs.... (Review)
Review
Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) is a subset of wild-type GIST that constitutes approximately 10% of gastric GISTs. SDH-mutated GISTs lack mutations in the proto-oncogene receptor tyrosine kinase (also known as KIT, c-KIT, or CD117) or platelet-derived growth factor receptor α (PDGFR-α). These tumors have female predilection, affect children and young adults, and have a spectrum of behavior from indolent to progressive. These tumors have characteristic morphologic features including multinodular architecture, multiple tumors, lymphovascular involvement, and occasional lymph node metastasis. They can be seen in patients with Carney triad or Carney-Stratakis syndrome. Although a mutation in any one of the SDH subunits can be pathogenic, deficiency of a single subunit leads to loss of detectable SDH subunit B by immunohistochemistry, enabling a convenient, tissue-based screening method. The prognosis and the clinical course of these tumors is different from that of KIT- or PDGFR-α-mutated GISTs. Surgical management is considered the main line of treatment. SDH-mutated GISTs do not respond well to the common targeted therapy, with no objective tumor response to imatinib. The role of the pathologist in diagnosing these cases is imperative in management and subsequent follow-up.
Topics: Chondroma; Electron Transport Complex II; Gastrointestinal Stromal Tumors; Humans; Immunohistochemistry; Leiomyosarcoma; Lung Neoplasms; Membrane Proteins; Mutation; Paraganglioma; Paraganglioma, Extra-Adrenal; Prognosis; Proto-Oncogene Mas; Stomach Neoplasms; Succinate Dehydrogenase
PubMed: 31169996
DOI: 10.5858/arpa.2018-0370-RS -
Journal of Biomedical Science Nov 2022Succinate is a tricarboxylic acid (TCA) cycle intermediate normally confined to the mitochondrial matrix. It is a substrate of succinate dehydrogenase (SDH). Mutation of... (Review)
Review
Succinate is a tricarboxylic acid (TCA) cycle intermediate normally confined to the mitochondrial matrix. It is a substrate of succinate dehydrogenase (SDH). Mutation of SDH subunits (SDHD and SDHB) in hereditary tumors such as paraganglioma or reduction of SDHB expression in cancer results in matrix succinate accumulation which is transported to cytoplasma and secreted into the extracellular milieu. Excessive cytosolic succinate is known to stabilize hypoxia inducible factor-1α (HIF-1α) by inhibiting prolyl hydroxylase. Recent reports indicate that cancer-secreted succinate enhances cancer cell migration and promotes cancer metastasis by activating succinate receptor-1 (SUCNR-1)-mediated signaling and transcription pathways. Cancer-derived extracellular succinate enhances cancer cell and macrophage migration through SUCNR-1 → PI-3 K → HIF-1α pathway. Extracellular succinate induces tumor angiogenesis through SUCNR-1-mediated ERK1/2 and STAT3 activation resulting in upregulation of vascular endothelial growth factor (VEGF) expression. Succinate increases SUCNR-1 expression in cancer cells which is considered as a target for developing new anti-metastasis drugs. Furthermore, serum succinate which is elevated in cancer patients may be a theranostic biomarker for selecting patients for SUCNR-1 antagonist therapy.
Topics: Humans; Neovascularization, Pathologic; Paraganglioma; Succinates; Succinic Acid; Vascular Endothelial Growth Factor A; Neoplasms; Neoplasm Metastasis; Extracellular Space
PubMed: 36344992
DOI: 10.1186/s12929-022-00878-z -
Endocrine Practice : Official Journal... Feb 2023To review the epidemiology, presentation, diagnosis, and management of head and neck paragangliomas. (Review)
Review
OBJECTIVE
To review the epidemiology, presentation, diagnosis, and management of head and neck paragangliomas.
METHODS
A literature review of english language papers with focus on most current literature.
RESULTS
Paragangliomas (PGLs) are a group of neuroendocrine tumors that arise in the parasympathetic or sympathetic ganglia. Head and neck PGLs (HNPGLs) comprise 65% to 70% of all PGLs and account for 0.6% of all head and neck cancers. The majority of HNPGLs are benign, and 6% to 19% of all HNPGLs develop metastasis outside the tumor site and significantly compromise survival. PGLs can have a familial etiology with germline sequence variations in different susceptibility genes, with the gene encoding succinate dehydrogenase being the most common sequence variation, or they can arise from somatic sequence variations or fusion genes. Workup includes biochemical testing to rule out secretory components, although it is rare in HNPGLs. In addition, imaging modalities, such as computed tomography and magnetic resonance imaging, help in monitoring in surgical planning. Functional imaging with DOTATATE-positron emission tomography, 18F-fluorodeoxyglucose, or 18F-fluorohydroxyphenylalanine may be necessary to rule out sites of metastases. The management of HNPGLs is complex depending on pathology, location, and aggressiveness of the tumor. Treatment ranges from observation to resection to systemic treatment. Similarly, the prognosis ranges from a normal life expectancy to a 5-year survival of 11.8% in patients with distant metastasis.
CONCLUSION
Our review is a comprehensive summary of the incidence, mortality, pathogenesis, presentation, workup and management of HNPGLs.
Topics: Humans; Fluorodeoxyglucose F18; Head and Neck Neoplasms; Paraganglioma; Paraganglioma, Extra-Adrenal; Succinate Dehydrogenase; Tomography, X-Ray Computed
PubMed: 36252779
DOI: 10.1016/j.eprac.2022.10.002 -
Circulation May 2021Neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species...
BACKGROUND
Neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species production that induces DNA damage. These cellular changes contribute to cardiomyocyte cell cycle exit and loss of the capacity for cardiac regeneration. The mechanisms that regulate this metabolic switch and the increase in reactive oxygen species production have been relatively unexplored. Current evidence suggests that elevated reactive oxygen species production in ischemic tissues occurs as a result of accumulation of the mitochondrial metabolite succinate during ischemia via succinate dehydrogenase (SDH), and this succinate is rapidly oxidized at reperfusion. Mutations in SDH in familial cancer syndromes have been demonstrated to promote a metabolic shift into glycolytic metabolism, suggesting a potential role for SDH in regulating cellular metabolism. Whether succinate and SDH regulate cardiomyocyte cell cycle activity and the cardiac metabolic state remains unclear.
METHODS
Here, we investigated the role of succinate and SDH inhibition in regulation of postnatal cardiomyocyte cell cycle activity and heart regeneration.
RESULTS
Our results demonstrate that injection of succinate into neonatal mice results in inhibition of cardiomyocyte proliferation and regeneration. Our evidence also shows that inhibition of SDH by malonate treatment after birth extends the window of cardiomyocyte proliferation and regeneration in juvenile mice. Remarkably, extending malonate treatment to the adult mouse heart after myocardial infarction injury results in a robust regenerative response within 4 weeks after injury via promoting adult cardiomyocyte proliferation and revascularization. Our metabolite analysis after SDH inhibition by malonate induces dynamic changes in adult cardiac metabolism.
CONCLUSIONS
Inhibition of SDH by malonate promotes adult cardiomyocyte proliferation, revascularization, and heart regeneration via metabolic reprogramming. These findings support a potentially important new therapeutic approach for human heart failure.
Topics: Animals; Cardiovascular Diseases; Cell Proliferation; Humans; Male; Malonates; Mice; Myocardium; Myocytes, Cardiac; Regeneration; Signal Transduction
PubMed: 33666092
DOI: 10.1161/CIRCULATIONAHA.120.049952 -
Nature Reviews. Endocrinology Jul 2021Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA,... (Review)
Review
Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.
Topics: Adult; Aged; Algorithms; Asymptomatic Diseases; Child; Consensus; Genetic Carrier Screening; Genetic Testing; Germ-Line Mutation; Heterozygote; Humans; Internationality; Mass Screening; Monitoring, Physiologic; Succinate Dehydrogenase
PubMed: 34021277
DOI: 10.1038/s41574-021-00492-3 -
Science (New York, N.Y.) Dec 2021For electrons to continuously enter and flow through the mitochondrial electron transport chain (ETC), they must ultimately land on a terminal electron acceptor (TEA),...
For electrons to continuously enter and flow through the mitochondrial electron transport chain (ETC), they must ultimately land on a terminal electron acceptor (TEA), which is known to be oxygen in mammals. Paradoxically, we find that complex I and dihydroorotate dehydrogenase (DHODH) can still deposit electrons into the ETC when oxygen reduction is impeded. Cells lacking oxygen reduction accumulate ubiquinol, driving the succinate dehydrogenase (SDH) complex in reverse to enable electron deposition onto fumarate. Upon inhibition of oxygen reduction, fumarate reduction sustains DHODH and complex I activities. Mouse tissues display varying capacities to use fumarate as a TEA, most of which net reverse the SDH complex under hypoxia. Thus, we delineate a circuit of electron flow in the mammalian ETC that maintains mitochondrial functions under oxygen limitation.
Topics: Animals; Cell Hypoxia; Cell Line; Cell Line, Tumor; Dihydroorotate Dehydrogenase; Electron Transport; Electron Transport Complex I; Electron Transport Complex III; Electron Transport Complex IV; Electrons; Female; Fumarates; Humans; Mice; Mice, Inbred C57BL; Mitochondria; Oxidation-Reduction; Oxygen; Succinate Dehydrogenase; Ubiquinone
PubMed: 34855504
DOI: 10.1126/science.abi7495 -
Nature Communications Jun 2021Dysregulated extravillous trophoblast invasion and proliferation are known to increase the risk of recurrent spontaneous abortion (RSA); however, the underlying...
Dysregulated extravillous trophoblast invasion and proliferation are known to increase the risk of recurrent spontaneous abortion (RSA); however, the underlying mechanism remains unclear. Herein, in our retrospective observational case-control study we show that villous samples from RSA patients, compared to healthy controls, display reduced succinate dehydrogenase complex iron sulfur subunit (SDHB) DNA methylation, elevated SDHB expression, and reduced succinate levels, indicating that low succinate levels correlate with RSA. Moreover, we find high succinate levels in early pregnant women are correlated with successful embryo implantation. SDHB promoter methylation recruited MBD1 and excluded c-Fos, inactivating SDHB expression and causing intracellular succinate accumulation which mimicked hypoxia in extravillous trophoblasts cell lines JEG3 and HTR8 via the PHD2-VHL-HIF-1α pathway; however, low succinate levels reversed this effect and increased the risk of abortion in mouse model. This study reveals that abnormal metabolite levels inhibit extravillous trophoblast function and highlights an approach for RSA intervention.
Topics: Abortion, Habitual; Animals; Case-Control Studies; Cell Hypoxia; Cell Line, Tumor; Chorionic Villi; CpG Islands; DNA Methylation; DNA-Binding Proteins; Female; Gene Expression Regulation; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Metabolome; Mice, Inbred C57BL; Pregnancy; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins c-fos; Risk Factors; Succinate Dehydrogenase; Succinic Acid; Transcription Factors; Transcription, Genetic; Trophoblasts; Mice
PubMed: 34103526
DOI: 10.1038/s41467-021-23827-0 -
Redox Biology Oct 2021Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix in the lung with fibroblast-to-myofibroblast transition, leading to...
Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix in the lung with fibroblast-to-myofibroblast transition, leading to chronically compromising lung function and death. However, very little is known about the metabolic alterations of fibroblasts in IPF, and there is still a lack of pharmaceutical agents to target the metabolic dysregulation. Here we show a glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts from fibrotic lung, and perturbation of glycolysis and FAO affects fibroblasts transdifferentiation. In addition, there is a significant accumulation of succinate both in fibrotic lung tissues and myofibroblasts, where succinate dehydrogenase (SDH) operates in reverse by reducing fumarate to succinate. Then succinate contributes to glycolysis upregulation and FAO downregulation by stabilizing HIF-1α, which promotes the development of lung fibrosis. In addition, we identify a near-infrared small molecule dye, IR-780, as a targeting agent which stimulates mild inhibition of succinate dehydrogenase subunit A (SDHA) in fibroblasts, and which inhibits TGF-β1 induced SDH and succinate elevation, then to prevent fibrosis formation and respiratory dysfunction. Further, enhanced cell retention of IR-780 is shown to promote severe inhibition of SDHA in myofibroblasts, which may contribute to excessive ROS generation and selectively induces myofibroblasts to apoptosis, and then therapeutically improves established lung fibrosis in vivo. These findings indicate that targeting metabolic dysregulation has significant implications for therapies aimed at lung fibrosis and succinate dehydrogenase is an exciting new therapeutic target to treat IPF.
Topics: Bleomycin; Fibroblasts; Humans; Idiopathic Pulmonary Fibrosis; Lung; Myofibroblasts; Pharmaceutical Preparations; Succinate Dehydrogenase
PubMed: 34343908
DOI: 10.1016/j.redox.2021.102082 -
ELife May 2020Metabolic pathways and inflammatory processes are under circadian regulation. Rhythmic immune cell recruitment is known to impact infection outcomes, but whether the...
Metabolic pathways and inflammatory processes are under circadian regulation. Rhythmic immune cell recruitment is known to impact infection outcomes, but whether the circadian clock modulates immunometabolism remains unclear. We find that the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-γ/lipopolysaccharide (M1) and tumor-conditioned medium, to maintain mitochondrial metabolism under metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial production of reactive oxygen species as well as Hif-1α-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, aberrant Hif-1α activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, whereas administering the SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint that integrates macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1α regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.
Topics: ARNTL Transcription Factors; Amino Acids; Animals; Circadian Clocks; Gene Knockout Techniques; Hypoxia-Inducible Factor 1, alpha Subunit; Interferon-gamma; Lipopolysaccharides; Macrophage Activation; Macrophages; Malonates; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mitochondria; Oxidation-Reduction; Oxidative Stress; Succinate Dehydrogenase; Transcription, Genetic; Tumor-Associated Macrophages
PubMed: 32396064
DOI: 10.7554/eLife.54090 -
Nature Communications Jul 2022Succinate dehydrogenase, which is known as mitochondrial complex II, has proven to be a fascinating machinery, attracting renewed and increased interest in its...
Succinate dehydrogenase, which is known as mitochondrial complex II, has proven to be a fascinating machinery, attracting renewed and increased interest in its involvement in human diseases. Herein, we find that succinate dehydrogenase assembly factor 4 (SDHAF4) is downregulated in cardiac muscle in response to pathological stresses and in diseased hearts from human patients. Cardiac loss of Sdhaf4 suppresses complex II assembly and results in subunit degradation and complex II deficiency in fetal mice. These defects are exacerbated in young adults with globally impaired metabolic capacity and activation of dynamin-related protein 1, which induces excess mitochondrial fission and mitophagy, thereby causing progressive dilated cardiomyopathy and lethal heart failure in animals. Targeting mitochondria via supplementation with fumarate or inhibiting mitochondrial fission improves mitochondrial dynamics, partially restores cardiac function and prolongs the lifespan of mutant mice. Moreover, the addition of fumarate is found to dramatically improve cardiac function in myocardial infarction mice. These findings reveal a vital role for complex II assembly in the development of dilated cardiomyopathy and provide additional insights into therapeutic interventions for heart diseases.
Topics: Animals; Cardiomyopathy, Dilated; Fumarates; Mice; Mitochondrial Dynamics; Mitophagy; Myocytes, Cardiac; Succinate Dehydrogenase
PubMed: 35803927
DOI: 10.1038/s41467-022-31548-1