Mechanisms of inhibition by these compounds differ significantly because oxaloacetate, a competitive inhibitor of succinate dehydrogenase, bounds with a sulfhydryl group of the enzyme to abolish the enzyme activity [ 16 ]. It is known that SDH is sensitive to different thiol-binding reagents. Inhibition of the enzyme by these kinds of reagents resulted from the modification of a sulfhydryl group located at the active site. This thiol, although not essential for substrate binding or catalysis, could influence the binding of dicarboxylates, probably by steric hindrance when a larger group or a charged group were attached to it.
The inhibition of SDH by histidine specific reagents was also reported, and the participation of an imidazole ring in the initial step of succinate oxidation was suggested. The inactivation of SDH by phenylglyoxal and 2,3 —butanedione showed the presence of an arginine-residues that interacts with dicarboxylate to form the primary enzyme-substrate complex [ 17 ]. SDH is not only known to catalyse a unique reaction, which requires the participation of its four subunits, but deleterious mutations in any of the SDH genes should invariably result in a decreased SDH activity.
Therefore, the striking phenotypic differences associated with mutations in the four subunits raise puzzling questions. SDH also plays a specific role in the maintenance of the mitochondrial UQ pool reduction. Ubiquinone, beside its function as an electron carrier mediating electron transfer, is admittedly working as a powerful antioxidant in biological membranes. Then, only a portion of the UQ pool may be actually involved in electron transfer depending on dehydrogenases involved.
Accordingly, the measurable redox status of the UQ pool should result from the reducing activity of the different dehydrogenases, the oxidising activity of complex III and the kinetic equilibrium in the pool. The UQ pool therefore represents an electron sink and, when reduced, an antioxidant reservoir in the mitochondrial inner membrane.
However, UQ is a double-faced compound, possibly working as either an antioxidant when fully reduced to ubiquinol, or a pro-oxidant when semi-reduced to the unstable ubisemiquinone form. Possibly together with reduced cytochrome b, semi-reduced quinones constitute the prominent source of superoxides. Finally, when defective, the abnormal amount of superoxides can be produced, e. Delivering electrons for the full reduction of UQ to UQH2 might then be of a tremendous importance for the control of oxygen toxicity in the mitochondria.
Therefore, the SDH, thanks to its unique redox properties, may be a key enzyme to control UQ pool redox poise under these conditions [ 13 ]. Disruption of complex II activity should alter TCA cycle metabolite levels in the mitochondrial matrix. The succinate is the most efficient energy source, so the SDH activity assay can be an important method for measurement of the yeast vitality in scope to control, e.
SDH activities can be measured in vitro in cell lysates or in mitochondrial fraction as well as in situ in individual cells. Since SDH is bound to the inner membrane, it is easily isolated along with the mitochondria by different techniques: sucrose density gradient ultracentrifugation, free-flow electrophoresis or a commercially available kit-based method [ 20 ].
The mitochondrial fraction is the source of the enzyme. To use an artificial electron acceptor, the normal path of electrons through the mitochondrial electron transport system must be blocked. This is accomplished by adding either sodium azide or potassium cyanide to the reaction mixture. These poisons inhibit the transfer of electrons from cytochrome a3 to the final electron acceptor, oxygen, thus electrons cannot be passed along by the preceding cytochromes and coenzyme Q.
The reduction of DCIP can be followed spectrophotometrically since the oxidized form of the dye is blue and the reduced form is colorless. This reaction can be summarized as. The change in absorbance, measured at nm, can be used to follow the reaction over time [ 21 ]. To use an artificial electron acceptor, the normal path of electrons in the electron transport chain must be blocked. This is accomplished by adding either potassium cyanide or sodium azide to the reaction mixture. The rate of the disappearance of the blue color is proportional to the concentration of enzyme.
The change in absorbance of the mixture is measured as a function of time and the enzyme concentration is determined from these data. Enzymatic reactions in yeasts are usually studied in cell-free extracts which requires disruption of cells and as consequence, inactivation of particular enzymes often can be observed. Generally we can conclud that determination of SDH enzyme activity has proved to be a difficult enzyme to extract from respiratory membrane whilst still retaining its in vivo properties.
Most of the described extraction procedures were rather drastic and yielded soluble preparations of rather dubious integrity [ 8 ]. In recent years quantitative histochemical procedures has been proved to be a powerful research tool, especially in microphotometric assessment in situ of the specific activity of dehydrogenases in individual cells. These assays are simple and valid alternative to conventional biochemical techniques.
Methods in situ can provide the cellular resolution necessary to determine enzyme-specific activities not only in whole cell preparations but also in distinct subcellular compartments [ 19 ]. Reduction of various tetrazolium salts by dehydrogenases of metabolically active cells leads to production of highly colored end products — formazans Figure 7.
The history of the tetrazolium salts and formazans goes back years, to when Friese reacted benzene diazonium nitrate with nitromethane, to produce a cherry-red "Neue Verbindung".
This was the first formazan. Nineteen years later, Von Pechmann and Runge oxidised a formazan to produce the first tetrazolium salt [ 21 ]. Tetrazolium salt and its coloured formazan. Many hundreds of tetrazolium salts and formazans were prepared in the following years, but only a handful have found applications in biological research. There is a wide range of tetrazolium salts commonly used in the field of microbiology from the classical ones to the new generation of its derivatives.
Among them are: blue tetrazolium chloride BT , 2,3,5-triphenyl tetrazolium chloride TTC , 3- 4,5-dimethylthiazolyl -2,5-diphenyltetrazolium bromide MTT , 5-cyano-2,3-ditolyl tetrazolium chloride CTC , 2,3-bis 2-methoxynitrosulphophenyl [ phenylamino carbonyl]-2H-tetrazolium hydroxide XTT , 4-[3- 4-idophenyl 4-nitrophenyl -2Htetrazolio]-1,3-benzene disulfonate WST1 , 2- p-iodophenyl -3 p-nitrophenyl phenyltetrazolium chloride INT or 2,2'-dibenzothiazolyl-5,5'-[4-di 2-sulfoethyl carbamoylphenyl]-3,3'- 3,3'-dimethoxy-4,4' biphenyl ditetrazolium, disodium salt WST-5 [ 19 , 22 , 23 ].
In the case of enzymatic reaction conducted in situ the plasma membrane forms a barrier with low degree of penetration. Therefore, cell permeabilization, e. According to the results obtained by Berlowska et al. After digitonin treatment, the visible formazan crystals were observed inside the yeast cells, but not outside them Figures 8 A, B.
The formazan products are water-insoluble, but readily diffuses out of yeast cells after solubilization in DMSO. Linear correlation was observed in the concentration range of yeast cells from 7 to 8 per sample. For yeast cell concentrations below 7 per sample the formazan color intensity signals were too low to detect with good precision.
The results obtained for SDH activity were in good agreement. Yeast cells after reaction with blue tetrazolium chloride BT. A — without permeabilization; B — with permeabilization by 0. Images of light microscopy. Yeast cells after reaction with 2,3,5-triphenyl tetrazolium chloride TTC. Images of fluorescence microscopy. Yeast cell after reaction with 2,3,5-triphenyl tetrazolium chloride TTC. Images of scanning microscopy. Significant decreasing of succinate dehydrogenase activity and ATP content were observed during aging of tested yeast strains [ 19 , 23 ].
Saccharomyces cerevisiae is a simple eukaryotic organism, with a complete genome sequence. Many genetic tools that have been created during these years, including the complete collection of gene deletions and a considerable number of mechanisms and pathways existing in higher eukaryotes was first studied and described in yeast.
The study of mitochondrial functions and dysfunction is of special interest in yeast because it is in this organism that mitochondrial genetics and recombination have been discovered and that nucleomitochondrial interactions have been studied in-depth. There are also specific reasons for choosing S. This organism is petite-positive, which can successfully grow in the absence of oxygen.
Therefore it can lose its mitochondrial genome provided it is supplied with a substrate for fermentation. Consequently, all mutations of the mitochondrial genome can be studied without cell lethality. It is genetically easy to transfer mitochondria from one nuclear genetic background to another via karyogamy.
Additionally, mitochondria can be transformed making in vitro mutation analysis possible. The richness and ease of yeast molecular genetics opens big opportunities, and even the major difference existing between human and yeast mitochondrial genomes, i.
To review mitochondrial diseases may be a very difficult task because the definition might include different kinds of metabolic disorders or degenerative syndromes [ 24 ]. Moreover, some important aspects have been extensively reviewed and the reader might refer to very good recent articles by DiMauro and Garone [ 25 ] for historical aspects, by Wallace et al. The previous review by Schwimmer et al.
SDH in yeast and human are very similar. In the last ten years, deficiencies in TCA cycle enzymes have been shown to cause a wide spectrum of human diseases. For instance, mutation in the gene encoding fumarase is a rare cause of encephalomyopathy and a far more common cause of leiomyomas of the skin and uterus and of renal cancer Table 1.
The TCA path dysfunction may also result from concurrent impairments in several steps of the cycle. The ratios between TCA enzymes are consistent for each mammalian tissues presumably reflecting their metabolic demand. Consequently, in addition to the determination of residual absolute activities, estimation of ratios between enzyme activities is an effective means of detecting partial but potentially harmful deficiencies. When used to assess respiratory chain activities, this approach enabled the identification of several gene mutations, even in patients with partial respiratory chain deficiencies.
At present, TCA enzyme activities are measured using a series of independent. Primary deficiencies in TCA cycle enzymes in humans [ 22 ]. The limited set of assays allowing both measurement of all TCA enzyme activities and detection of abnormalities in enzyme activity ratios were developed. These assays were used successfully to detect severe and partial isolated deficiencies in several TCA enzymes. The reduction of DCPIP was measured using two wavelengths nm and nm with various substrates and the electron acceptors decylubiquinone and phenazine methosulfate.
The second assay measured -ketoglutarate dehydrogenase, aconitase, and isocitrate dehydrogenase activities. Hence, SDH 'inactivation' induces abnormal stimulation of the hypoxia-angiogenesis pathway. When complex II is absent, it can be disregarded as a source of additional superoxide production.
Thus, the superoxide overproduction would lead to tumour formation that should be ascribed to the decreased ability of the SDH to adequately reduce the Q pool, a necessary condition to resist oxidative stress [ 8 ]. Ubiquinone, beside its function in the respiratory chain as an electron carrier mediating electron transfer between the various dehydrogenases and the cytochrome path, is working as a powerful antioxidant in biological membranes [ 13 ].
It is possibly for this exact reason in much larger amounts compared to other electron carriers of the respiratory chain, including the sum of the dehydrogenases. When it is defective, the respiratory chain can produce an abnormal amount of superoxides involving additional respiratory chain components such as flavin radicals of complex I. Delivering electrons for the full reduction of Q to QH2 might then be of a tremendous importance for the control of oxygen toxicity in the mitochondria.
Therefore, the SDH is a key enzyme to control Q pool redox poise under these conditions, due to its unique redox properties [ 8 ]. Iron-sulfur Fe-S proteins facilitate multiple functions, including redox activity, enzymatic function, and maintenance of structural integrity. More than 20 proteins are involved in the biosynthesis of iron-sulfur clusters in eukaryotes.
Defective Fe-S cluster synthesis not only affects activities of many iron-sulfur enzymes, such as aconitase and succinate dehydrogenase, but also alters the regulation of cellular iron homeostasis, causing both mitochondrial iron overload and cytosolic iron deficiency.
Fe-S cluster biogenesis takes place essentially in every tissue of humans, and products of human disease genes have important roles in the process [ 40 ]. Succinate is an oxygen sensor in the cell and can help turn on specific pathways that stimulate cells to grow in a low-oxygen environment hypoxia. In particular, succinate stabilizes a protein called hypoxia-inducible factor HIF by preventing a reaction that would allow HIF to be broken down.
HIF controls several important genes involved in cell division and the formation of new blood vessels in a hypoxic environment. However, a single mutation in the SDHA gene increases the risk that an individual will develop the condition, and additional mutation that deletes the normal copy of the gene is needed to cause tumor formation. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is present only in tumor cells.
As a result, there is little or no SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. The excess succinate abnormally stabilizes HIF, which also builds up in cells. Excess HIF stimulates cells to divide and triggers the production of blood vessels when they are not needed. Rapid and uncontrolled cell division, along with the formation of new blood vessels, can lead to the development of tumors.
Mutations in the SDHA gene were identified in a small number of people with Leigh syndrome, a progressive brain disorder that typically appears in infancy or early childhood. Affected children may experience vomiting, seizures, delayed development, muscle weakness, and problems with movement. Heart disease, kidney problems, and difficulty breathing can also occur in people with this disorder.
The one child died suddenly at the age of five months from a severe deterioration of neuromuscular, cardiac, and hepatic symptoms after an intermittent infection.
These genetic changes disrupt the activity of the SDH enzyme, impairing the ability of mitochondria to produce energy. This suggested a role of additional nuclear genes involved in synthesis, assembly, or maintenance of SDH. It is not known, however, how mutations in the SDHA gene are related to the specific features of Leigh syndrome [ 41 , 42 ]. Two plausible hypotheses have been proposed to explain the peculiar linkage between disruption of electron flow through mitochondrial complex II and tumorigenesis in neuroendocrine cells.
Although certain mutations in these genes result in ROS production in Saccharomyces cerevisiae and mammalian cell lines, it is not clear that ROS accumulate to levels that are mutagenic.
ROS model [ 18 ]. Succinate accumulation model [ 18 ]. Excess succinate is shuttled from the mitochondrial matrix to the cytoplasm, where it inhibits any of several aKG-dependent enzymes E that regulate levels or activities of important regulatory proteins black box.
Succinate can then act as an inhibitor of a-ketoglutarate-dependent enzymes that use ferrous iron and molecular oxygen as cofactors to hydroxylate their substrates and generate succinate as a product. It has been demonstrated that two a-ketoglutarate -dependent enzymes, the prolyl hydroxylases, are inhibited by succinate accumulation in cells that have lost SDHD function.
Metabolic engineering, i. In contrast to classical methods of genetic strain improvement such as selection, mutagenesis, mating, and hybridization, metabolic engineering confers two major advantages: 1 the directed modification of strains without the accumulation of unfavorable mutations and 2 the introduction of genes from foreign organisms to equip S.
The latter is particularly crucial for industrial biotechnology to provide pathways that extend the spectrum of usable industrial media e. Since the first introduction of metabolic engineering, there have been tremendous enhancements of its toolbox, and several related disciplines have emerged, such as inverse metabolic engineering and evolutionary engineering.
These developments have strongly influenced yeast strain improvement programs in the past few years and have greatly enhanced the potential for using yeast in biotechnological production processes [ 43 ]. The main goals of metabolic engineering can be summarized in the following four categories: 1 improvement of yield, productivity and overall cellular physiology, 2 extension of the substrate range, 3 deletion or reduction of by-product formation and 4 introduction of pathways leading to new products.
Commonly these goals can be achieved by a three-step procedure. Firstly, a genetic modification is proposed, based on metabolic models. After genetic modification, the recombinant strain is analysed and the results are then used to identify the next target for genetic manipulation, if necessary. Thus, the construction of an optimal strain involves a close interaction between synthesis and analysis, usually for several consecutive rounds. The rapid development and frequent success in this field is demonstrated by the large number of reviews about the theoretical and practical aspects of metabolic engineering.
Knowledge of cellular and microbial physiology, as well as the underlying metabolic networks or enzymes, is an important prerequisite for successful engineering. Recently, a computational approach for the identification of every possible biochemical reaction from a given set of enzyme reaction rules was reported. This analysis suggested that the native pathways are thermodynamically more favorable than the alternative possible pathways.
The pathways generated involve compounds that exist in biological databases, as well as compounds that exist in chemical databases and novel compounds, suggesting novel biochemical routes for these compounds and the existence of biochemical compounds that remain to be discovered or synthesized through enzyme and pathway engineering [ 45 ].
Due to its importance in traditional biotechnology such as baking, brewing, and wine making, research activities historically have focused on the yeast Saccharomyces cerevisiae. It is relatively tolerant to low pH values and high sugar and ethanol concentrations, i.
These features are the major reasons for increasing S. Among these compounds, several organic acids may fulfill a role as platform molecules using their multiple functional groups as a target for enzymic or chemical catalysis [ 43 ].
In the United States were identified 10 organic acids as key chemical building blocks [ 44 ]. Similarly, the European focus group BREW identified 21 key compounds that can be produced from different, including renewable sources, a number of which were organic acids [ 45 ]. One example of such a chemical is succinic acid. Succinic acid is used as a surfactant, detergent or foaming agent, as an ion chelator, and also in the food industry as an acidulant, flavoring agent or anti-microbial agent, as well as in health-related products such pharmaceuticals and antibiotics.
Currently, it is produced from petrol and is too expensive to be used as a general building-block chemical. However, provided that its price becomes competitive, succinic acid could replace petrol-derived maleic anhydride in chemical synthesis processes in the future [ 46 - 47 ]. Similar chemical derivatizations can be applied to malic and fumaric acid, so that they can also be considered interesting C 4 building blocks [ 48 - 53 ].
The chemical behavior of the dicarboxylic acid — succinic acid is determined principally by its two carboxyl groups. This substance is either directly utilized in the pharmaceutical or chemical industry or represent building block or precursor for further chemical or enzymatic syntheses. The following reactions and derivatives are considered interesting: 1 reductions of succinic acid to 1,4-butanediol, -butyrolactone, tetrahydrofuran and its derivatives; 2 reductive amination of succinic acid or -butyrolactone to pyrrolidiones; 3 polymerization of succinic acid with diols building block of polyesters ; 4 polymerisation of succinic acid with diamines to form polyamides, etc.
The examples of the substances that can be derived from succinic acid are shown in table 2. Preclinical models can show a general direction on how a clinical trial will go and account for metabolic environments not replicable in vitro. These models are a critical testing ground for higher stakes clinical trials. Clinical trials associated with SDH dysfunction range from advanced cancers to neurodegeneration Table 1.
The broader study of mitochondrial dysfunction also accounts for many clinical trials where SDH dysfunction plays a role. Temozolomide is an alkylating agent that has already been approved for use against glioblastoma multiforme and refractory anaplastic astrocytoma tumors. The inhibition of this protein due to promotor methylation has shown to lead to effective use of alkylating agents in other cancer types [ ].
The rationale was to use a known chemotherapy drug, temozolomide, against a type of tumor it had not been tested against. The rationale behind this studying is the methylation of SDH contributing to increased ROS and anaerobic environments causing cells to develop mutations.
By inhibiting methylation, tumor growth and mutation can be slowed. Glutamine metabolism has been shown to be upregulated in SDHB mutated cancers. This reliance on glutamine metabolism by SDH mutant cancers has created an increased sensitivity to glutaminase inhibitors. The rationale behind the trial is to introduce the glutaminase inhibitor to regular chemotherapy as a new way to slow tumor growth.
Nivolumab is a monoclonal antibody that inhibits programmed cell death-1 PD In SDH deficient tumors, PD-1 receptor-ligand signaling is dysregulated due to hypoxic conditions [ ]. This combination therapy with the tyrosine kinase inhibitor, cabozantinib, will target both programmed cell death signaling and vascular endothelial growth factors [ ]. SDH mutation can lead to several different cancers including paragangliomas.
However, there is little information on environmental and professional factors playing a role in cancer risk. This study is a cross-section of patients with the same sex, age, and gene affected without tumors. Many current therapies are ineffective against dysfunctional or mutated SDH subtypes of their parent tumor class. By continuing these trials, cancer is being targeted through a mechanism that affects both tumor progression and maintenance. By inhibiting the mutant SDH or restoring normal function, not only can tumor progression halt, but tumor recession can also take place.
The rationale is that participants with an altered or pathogenic chemoreflex will be intolerant to high altitude and exhibit cerebral edema or pulmonary edema. While no results were published, the implications are that dysfunctional SDH subunits contribute to an inability of the carotid body to respond to changes in altitude.
This now established relationship could inspire treatments with antioxidants or gene therapies. The North American Mitochondrial Disease Consortium Patient Registry and Biorespiratory group aims to identify individuals with mitochondrial disorders and connect them with other current clinical trials for which they may be eligible. Macrophage mediated pro-inflammatory response is a common issue in diabetic and other related cardiovascular complications.
Recent studies suggest that glutamine catabolism is involved in the activation of these macrophages through TCA cycle intermediates. Non-cancer related SDH trials cover a wide variety of diseases. SDH trials related to mitochondrial disease cover many different subsets related to genetic conditions. The chemoreflex also shows SDH in the capacity of internal respiration. This wide range of trials shows the dependency of the human body on SDH. In this study, we systematically summarized how the SDH complex interacts with the RNA networks to regulate the development of cancer and other diseases.
There are several promising points that need to be investigated further in the future to better understand the mechanisms of SDH in pathogenesis. Utilizing the cutting-edge cryo-electron spectroscopy [ ] will facilitate our understanding of this interaction and further insight on cancer and disease development.
Among them, only a limited number of miRNAs have been studied. It is of interest to study whether succinate accumulation can also influence the activity of RNA editors.
For example, cell-free circulating exosomal miRNAs can transmit signals when they are delivered from the original site to the target site [ ]. Similar to circulating miRNAs, succinate has been discovered to shuttle from hypoxic retina to oxygen-enriched tissue to transfer electrons [ ]. Severe fungal infections to humans have caused many deaths in patients [ ]. Most of the fungicides are designed to combat human fungal pathogens through inhibiting cellular mitochondrial respiration such as SDH activities in fungi [ ].
SDH inhibitors targeting fungus infection has been difficult to incorporate into human application due to the similar SDH structures in human and fungal cells. Thus, the following two concerns need to be addressed when applying the SDH inhibitors in antifungal antipathogen treatment in humans.
The applied SDH inhibitors can be transmitted to human cells leading to increased risk of tumorigenesis due to inactivating tumor suppressor SDH in human cells. Additionally, pathogen-derived succinate might also influence tumor initiation and progression in humans [ , ].
RNA-based therapeutics have received increasing attention recently due to its advantage of accuracy and specificity compared to conventional small molecules [ ]. However, the delivery efficiency and off-target effect of RNA therapeutics need to be addressed properly before entering clinical trials. It is critical to improve the RNA delivery to targeted cells by using cutting-edge nanoparticles and ligand-conjugated carriers [ ]. Simultaneously, exploring the distribution and functions of RNA-based-therapeutics in non-targeted cells i.
We apologize to all researchers whose work could not be cited due to reference limitations. All figures were created with BioRender. Conceptualization, C. Figure 1 , R. Figure 2 and Figure 3 , R. Figure 4 and Table 1 , and R. Z; funding acquisition, W. All authors have read and agreed to the published version of the manuscript. National Center for Biotechnology Information , U. Journal List Cancers Basel v.
Cancers Basel. Published online Nov 3. Author information Article notes Copyright and License information Disclaimer. Received Sep 25; Accepted Oct This article has been cited by other articles in PMC.
Abstract Simple Summary Although the dysfunction of the succinate dehydrogenase complex in mitochondria leads to cancer and other diseases due to aberrant metabolic reactions and signaling pathways, it is not well known how the succinate dehydrogenase complex is regulated.
Keywords: succinate dehydrogenase, cancer, disease, tricarboxylic acid cycle, electron transport chain, metabolism, reactive oxygen species, non-coding RNA, RNA-editing, RNA-modification. Introduction Succinate dehydrogenase SDH is a mitochondrial enzyme present in supporting metabolic function through the tricarboxylic acid cycle TCA cycle and the electron transport chain ETC.
Open in a separate window. Figure 1. Figure 2. High-Altitude Illness Acute Mountain Sickness Acute mountain sickness AMS is a result of the decreased partial pressure of oxygen at higher altitudes that causes tissue hypoxia [ 47 ]. Inflammation SDH has shown the capability to play key roles in pro- and anti-inflammatory signaling Figure 2. Neurodegenerative Disease SDH has an important role in electron flow [ 19 , 59 ], exemplified by SDH activity causing electron carriers such as nicotinamide adenine dinucleotide NAD to not be oxidized which in turn leads to a decrease in electron flow to complex III and ubiquinone, and the production of ROS [ 60 ].
Diabetes The succinate mechanism of insulin release states that high mitochondrial levels of succinate produce mevalonic acid, which triggers insulin release in pancreatic islet cells refer to source paper for full mechanism [ 70 ].
Ischemia-Reperfusion Injury Succinate is known to accumulate during cardiac ischemia, which is then consumed during reperfusion and leads to oxidative damage due to increased ROS production [ 75 ]. Figure 3. Transcription Factors Transcription factors play an intricate role in gene expression as they activate or repress transcription of DNA into RNA [ 99 ], and its misregulation has been implicated to cause disease [ ].
Alternative Splicing The manipulation of the order of exons in mature mRNA due to alternative splicing mechanisms is well known to alter gene expression [ ]. Treatment against Succinate Dehydrogenase Dysfunction 5. Figure 4. Clinical Trials Clinical trials associated with SDH dysfunction range from advanced cancers to neurodegeneration Table 1. Table 1 SDH relevant clinical trials. GIST is resistant to conventional radiation or chemotherapy treatments.
Imatinib is the current standard of care but tumor-developed resistance and mutations are becoming more prevalent. Because this is a unique trait to tumors, this dependence serves as a potential therapeutic target. CB is a highly specific inhibitor targeting glutaminase, the first enzyme involved in glutamine utilization.
This study looks at the potency of this inhibitor across a wide range of tumors. Both drugs are approved treatments against several types of metastatic kidney cancers, but there are limited data on combination treatments using these two drugs.
At high altitudes where oxygen is limited, a cell already coping with SDH dysfunction would be overwhelmed. The chemoreflex causes hyperventilation when the pressure of oxygen falls in the blood.
A dysfunctional chemoreflex can lead to pulmonary and cerebral edema at high altitudes. After glutamine metabolism is better understood in its role in the inflammatory response, several other factors will be analyzed including SDH-controlled intermediates. RNA modification will also be utilized to target monocytes. Future Directions In this study, we systematically summarized how the SDH complex interacts with the RNA networks to regulate the development of cancer and other diseases.
Author Contributions Conceptualization, C. Conflicts of Interest The authors declare no conflict of interest. References 1. Rutter J. Succinate dehydrogenase—Assembly, regulation and role in human disease. Selak M. Cancer Cell. Barbieri I. Role of RNA modifications in cancer.
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