Oxidative phosphorylation dysregulation (OXPHOS) has been demonstrated to be essential for the development of cancer. Therefore, it may be argued that chaperone and deacetylase activities modulate OXPHOS activity. For instance, a complicated network of interactions connects a cell’s bioenergetic features and neoplastic potential through the imbalance of sirtuin 3 (SIRT3) and succinate dehydrogenase (SDH) enzymatic activity in mitochondria. The studies outlined in this review indicate that targeting SDH regulators is a promising novel therapeutic strategy for this extremely resistant disease. Additionally, a viable therapeutic strategy may involve triggering the cell death mechanism in cancer cells by blocking mitochondrial metabolism with a natural substance. A naturally occurring flavonoid called naringenin (NAR) has been extensively investigated for its pharmacological properties, which include anti-tumor actions. However, due to its low bioavailability in this situation, nanoencapsulation is designed to improve NAR anticancer efficacy. NAR can be encapsulated by chitosan nanoparticles-TPP conjugates, thereby improving NAR cellular absorption and cytotoxicity against cancer cells. Consequently, we proposed naringenin nanoparticles as a novel therapeutic target for SDH regulators in cancer.
Succinate dehydrogenase, Cancer, Chitosan, Naringenin, Oxidative phosphorylation
Evidence indicating that OXPHOS plays a substantial role in the development of many cancer cells has led to the growing recognition of cancer as a metabolic disease. OXPHOS controls the environment for tumor growth, invasion, and metastasis in addition to providing enough energy for tumor tissue survival. In this review, we talk about new research on changes to SDH activity, such as SDH dysregulation or endogenous SDH inhibitors that cause succinate buildup. We also present a thorough analysis of the role of succinate in the initiation of metabolic and epigenetic changes that contribute to the development of cancer, as well as its effects on angiogenesis, cell invasion, and migration.
Succinate Dehydrogenase (SDH)
SDH is a mitochondrial enzyme (complex II) that participates in both the TCA cycle and the mitochondrial electron transport chain. SDH transports electrons to the ubiquinone (coenzyme Q) pool in the respiratory chain and catalyzes the oxidation of succinate to fumarate in the TCA cycle. SDH subunit A (SDHA) and subunit B (SDHB) comprise the catalytic subunits in the hydrophilic head that protrudes into the mitochondrial matrix. The catalytic subunits in the hydrophilic head that extends into the mitochondrial matrix are SDH subunits A (SDHA) and B (SDHB). The ubiquinone-binding and membrane-anchoring SDH subunits, SDHC and SDHD, respectively, are responsible for these functions. The flavination of SDHA, which is necessary for the formation of the SDH complex, depends on SDH assembly factor (SDHAF). The SDHA gene has 16 exons and is found on chromosome 5p15.33 . SDHA is the primary catalytic component that changes succinate into fumarate. It includes the succinate binding site. While there are 8 exons in the SDHB gene, which is found on chromosome 1p35-36.1 . It contains three Fe-S centers and mediates electron transfer to the ubiquinone pool. The gene encoding SDHC is located at 1q21 and has 6 exons , and the SDHD gene is found on chromosome 11q23 and has 4 exons . By binding ubiquinone, SDHC and SDHD produce protons that eventually turn into ATP .
Regulation of SDH
Tumor necrosis factor receptor-associated protein 1 (TRAP1): TRAP1, a crucial member of the mitochondrial heat shock protein 90 family, is active in a variety of biological functions in various tumor types. TRAP1, also known as Hsp75, is the mitochondrial paralog of the molecular chaperone Hsp 90, with which it shares a high degree of amino acid sequence homology and domain organization . Hsp90 family chaperones are molecular machines that regulate the degradation of proteins after aggregation, unfolding, or misfolding. They do this by allowing the proteins to undergo conformational changes, to reach specific subcellular localizations, or to form multimeric complexes . The biochemical outputs of these functions consist in the integration of signaling and metabolic circuits, ultimately leading to a global proteostasis that can be seen as a dynamic process of quality control and efficiency maintenance of the proteome under changing environmental conditions . In the instance of TRAP1, its mitochondrial location makes it an appropriate option for the tuning of metabolic activities that take place in these organelles as well as for reacting to toxic situations that influence mitochondrial physiology. In fact, a number of observations show that pathological situations increase TRAP1 expression or activity .
Additionally, TRAP1 mutations have been found in a case of acute auto-inflammation that was also accompanied with cellular redox disequilibrium , in a child with the mitochondrial disease Leigh syndrome  that connected to gastrointestinal dysmotility, exhaustion, and persistent pain  and in a small subset of patients with complex developmental syndromes marked by malformations in the kidney and other regions . Therefore, it was suggested that TRAP1 protects mitochondria from harm in renal fibrosis models , and a proband with thyroid and kidney malignancies was found to have a TRAP1 mutation . The primary source of information on a putative harmful role for the chaperone is cancer model studies because TRAP1 is highly expressed in patient cohorts with hepatocellular carcinoma (HCC) . Small cell lung cancer high-grade glioma, breast cancer , ovarian, kidney, prostate, esophageal, and colorectal cancer are among the diseases where it is linked to advanced stage, metastasis, and a bad prognosis . TRAP1 induction predates neoplastic alterations and is only present in lesions that develop to carcinoma in colorectal cancer linked with ulcerative colitis and in an animal model of HCC progression. While high TRAP1 expression was linked to a poor prognosis, robust TRAP1 expression was linked to an increased likelihood of lymph node metastasis. However, is yet unknown its pathogenic significance in cancer . These findings point to a significant role for TRAP1 in the metabolic adjustments that support the growth of neoplasms and have stimulated studies aiming at mechanistically understanding its biochemical functions in various cancer contexts. Information on its structure, mode of action, interactors, and functional consequences have become clearer in recent years, along with the discovery of selective inhibitors. This information is beginning to paint a picture of TRAP1 acting as a master switch in tumor bioenergetics.
High amounts of succinate are produced when TRAP1 blocks the activity of respiratory complex II, which in turn reduces SDH activity. TRAP1 inhibits PTP opening in mitochondria via regulating the activities of OXPHOS complexes II and IV (SDH and cytochrome c oxidase, respectively) [18,19]. The consequences of the ability of chaperon to switch between a dimer and a tetramer conformation are unknown. Src tyrosine kinase and Ras/MEK/ERK signaling are downstream effects of phosphorylation which enhance TRAP1 activity. After TRAP1-dependent SDH inhibition, succinate buildup results in epigenetic alterations, migration, and angiogenesis as shown in Figure 1. Also promote cellular invasion and migration by STAT3/MMP2 pathway .
Figure 1. The biochemical mechanism of TRAP1 on SDH (a) In the mitochondria, TRAP1 binds to and prevents the activity of electron transport chain (ETC) complexes II and IV. As a result of its interaction with the protein deacetylase SIRT3, TRAP1 is known to suppress cyclophilin D (CypD), which prevents the opening of the permeability transition pore (PTP) and the subsequent induction of apoptosis by the release of cytochrome c. (b) In addition, phosphorylation of TRAP1 via several mechanisms increases its activity. Be aware that it is still unknown whether this occurs prior to or following the mitochondrial import of TRAP1. (c) Succinate builds up as a result of TRAP1's suppression of the ETC complex II, which in turn prevents prolyl hydroxylases from functioning in the cytosol to stabilize HIF1. A pseudo-hypoxic program is triggered by stabilized HIF1 and Myc, and this further upregulates the expression of the TRAP1 gene. (d) TRAP1 interacts with ETC complexes I, III, and V (ATP synthase) inside mitochondria as well, but the implications of this interaction are unknown. (e) Although TRAP1 tetramers and dimers coexist in the mitochondrial matrix, factors affecting the ratio of dimer to tetramer and their potential functional importance are still unknown. (f) The levels of TRAP1 have an impact on mitochondrial carbon preference. Glucose and pyruvate-derived carbon entry into the TCA cycle is downregulated in TRAP1 KO cells. A sizeable part of glucose is redirected to the pentose phosphate pathway (PPP), where it is used to synthesize NADPH reducing equivalents and make ribose sugars. This process may be done to combat the elevated reactive oxygen species (ROS) that are present in TRAP1 KO cells. Pyruvate generally enters the TCA cycle after decarboxylation and helps to create acetyl-CoA, a crucial TCA cycle intermediate [20,60].
Phosphorylation: Through many mechanisms, particularly phosphorylation, the activity of SDH is also controlled at the post-translational level. For example, c-Src kinase must phosphorylate the Y215 of the SDHA in order for Complex II electron transfer to be effective [21,22]. Other studies have demonstrated that under some circumstances, such as oxidative stress, SDHA phosphorylation is increased, enhancing Complex II-dependent respiration . Additionally, it has been demonstrated that the dephosphorylation process mediated by PTEN-like mitochondrial phosphatase-1 (PTPMT1) is associated to a glucose level adaptation and is involved in the deregulation of SDH activity .
Acetylation by a NAD-dependent deacetylase (SIRT3): Thirteen of the lysines in SDHA have been shown to be acetylated, and it has been shown that SIRT3, a NAD-dependent deacetylase, is a key regulator of SDH function because its absence reduces the activity of the enzyme . However, further studies are needed to shed light on the crosstalk between SDH and SIRT3 and the relative adaptation of the cell to metabolic alterations. SDH loss, reduction or dysregulation induce an altered metabolic phenotype by action of succinate accumulation [5,26]. It was revealed for Naringenin, activates AMPK-SIRT3 signaling to prevent mitochondrial oxidative stress damage and maintain mitochondrial function during ischemia-reperfusion injury. A promising candidate for the therapy of mitochondrial dysfunction caused by a variety of disorders may be naringenin .
Dysregulated induces an altered metabolic phenotype
Otto Warburg effect: It was first postulated in the early 1920s that tumor cells may alter their glucose metabolism and, consequently, their energy metabolism, producing energy mostly through glycolysis and giving rise to a process known as "aerobic glycolysis" . Although this hypothesis initially seems illogical, it has now been proven to be true . The biological characteristic of cellular energy adaptation to support high neoplastic proliferation most effectively was reprogramming of the TCA cycle, which later supported the etiology of cancer during its multistep evolution [29,30].
Epigenetic alteration: According to recent investigations, succinate is a new "epigenetic hacker" that inhibits DNA and histone demethylases . Additionally, succinylation is a post-translational alteration in which an amide bond holds a succinyl moiety to a lysine residue. A major conformational change is most likely the effect of this alteration, which conceals the positive charge on lysine. Multiple subcellular compartments, particularly mitochondria, experience global lysine hyper-succinylation as a result of succinate buildup brought on by SDH depletion leading to an epigenetic change in carcinomas . Studies have validated the role of succinate in cellular transformation and cancer at both the biochemical and genomic levels [33,34].
ROS production: Oxyradicals generated from mitochondria called reactive oxygen species (ROS) are involved in oxygen metabolism. Superoxide anion (O2-), a kind of ROS, is one example. It is becoming more and more known that O2- causes oxidative damage to a variety of physiological and pathological processes, including signal transduction , cell apoptosis  and gene mutagenesis . Reduced complex II enzyme activity, ROS generation, and increased DNA mutation can narrowly be avoided in transgenic mouse cells transfected with SDHC loss-of-function . Later investigations revealed that complex II enzymatic activity in mitochondria will be disrupted by any abnormalities in SDHB, SDHC, or SDHD but not SDHA. The inactivation of the TCA cycle enzyme causes mitochondria to malfunction, which directly and indirectly causes an excess generation of ROS. When ROS levels rise in the cytosol, they can oxidize amino acid residues in fatty acids and proteins result in genomic instability and irreversible DNA damage, which promote carcinogenesis and tumorigenesis [39,40].
Migration & angiogenesis: Additionally, it has been demonstrated that succinate causes cell migration via activating the SUCNR1 receptor. The succinate receptor, also known as GPR91, belongs to the P2Y purinoreceptor family of G protein-coupled receptors . Several tissues, including blood cells, adipose tissue, the liver, retina, and kidney, express it. This receptor, along with its ligand succinate, has just come to be recognized in these tissues as novel mediators of local stress conditions such ischemia, hypoxia, toxicity, and hyperglycemia. By activating PKCs phosphorylation and p38 MAPK subsequent activation SUCNR1 caused migration as in Figure 2 . Additionally, succinate induces neovascularization through the activation of extracellular regulated kinase (ERK) 1/2 and signal transducer and activator of transcription 3 (STAT3) via the particular succinate receptor GPR91, which demonstrates that this occurs in an HIF-independent manner [41,42]. There is a growing body of research that connects the ERK1/2 signaling pathway to angiogenesis [43,44]. Moreover, according to Loriot et al. , hypermethylation caused by succinate buildup is sufficient to trigger Epithelial mesenchymal transition (EMT). Additionally, Wang et al. demonstrated that SDHB knockdown activates the TGFß signaling pathway in colorectal cancer cells by increasing the activity of the tight-junction transcriptional repression complex SNAIL1-SMAD3/SMAD4, which produces EMT and facilitates cell migration and invasion .
Figure 2. Schematic illustration of the signaling pathway via which succinate drive cancer. The signaling pathway via which succinate phosphorylate Drp-1 and induces mitochondrial fission. ROS generated drive cancer cell migration. Extracellular regulated kinases (ERK1/2), phosphatidyl kinases (PI3K)/ STAT3 induce metastasis & angiogenesis.
SDH Target for Anticancer Therapy
Recently, natural substances have attention due to block tumor-specific changes in the mitochondrial metabolism and could be an attractive therapeutic strategy for activating the cell death machinery in cancer cells [47-49]. Flavanone group member naringenin (NAR) [2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) was discovered by Power and Tutin in 1907 . The hydrophobic molecule NAR (C15 H12 O5) has a molecular weight of 272.25 g/mol. It is primarily found in the form of aglycones and is a derivative of naringin or narirutin hydrolysis. Oranges, tomatoes, grapefruits, and lemons are the main sources of NAR [50,51]. Numerous investigations have shown that NAR and its derivatives possess significant pharmacological capabilities. These properties include estrogen-like activity or anti-cancer effects through inactivating carcinogens and cell cycle arrest. Additionally, p53 and members of the mitogen-activated protein kinase (MAPK) family, which are overexpressed and play a critical role in mediating pro-apoptotic effects in many cancers, induce apoptosis as shown in Figure 3 [52,53]. Flavonoids were shown to interfere with the UbQ-binding site between the SDHC and SDHD subunits in recent research, which demonstrated that they greatly inhibited SDH activity in cancer cells [48,54,55].
Figure 3. The mechanisms of naringenin in the proliferation pathway. JAK: Janus kinase, a group of intracellular, non-receptor tyrosine kinases that use the JAK-STAT pathway to translate cytokine-mediated signals: transcription factors STAT, PI3K, AKT, protein kinase B, an important cell survival mediator, and mTOR, the mammalian target of rapamycin: NF-B, also known as nuclear factor-kappa-light-chain-enhancer of activated B cells, COX-2, or cyclooxygenase 2, and Notch, a highly conserved cell signaling pathway seen in the majority of animals .
However, water solubility, low oral bioavailability, and instability of NAR, which are mostly caused by its hydrophobic and crystalline structure. Which provide obstacles to its effective medicinal application. Nano-drug delivery methods have been employed for formulation to address these physicochemical problems [53,56]. These nanocarriers, mostly through surface modification, shield the encapsulated molecule from lysis and pH changes, enhance its solubility, and enable sustained medication release to target cells. These factors have led to the development of a variety of nanocarriers, such as polymeric nanoparticles based on chitosan . In particular, the advancement of oncological therapy has drawn attention to the use of nanoparticles made of biodegradable polymer materials like chitosan (CS). D-glucosamine and N-acetyl-D-glucosamine, which were joined by a (1,4) glycosidic link, each make up two subunits of CS [52,58]. Because it provides a strong and reactive positive charge, the amine group on the glucosamine unit of the CS is a crucial component. The positive charge of CS can combine with an anion molecule to produce a complex. Additionally, CS can speed up the route of medication through cell membranes [54,59]. CS (positive) and tri-sodium polyphosphate (TPP) were ionically crosslinked to create chitosan nanoparticles that were naringenin-loaded. Usually, one of the most important factors influencing the short- and long-term stability of NPs is their surface charge. In our earlier research, we found that the particles' surface charge had increased as measured by zeta potential. Less neutralization of the NH3 groups by the TPP crosslinker may be the cause of the rise in surface charge. High positive charge particles are more stable and have cohesion and tissue permeability characteristics. Due to their positive zeta potential, chitosan nanoparticles are more stable and can carry drugs more effectively by more easily adhering to negatively charged cell membranes . Due to its distinct sub-cellular size in comparison to the microscopic system, the formulation of CS with NAR is anticipated to produce significant intracellular absorption . As a result, while using the initial molecule, in this example NAR, the potential for being anti-cancer can be improved.
The unbalance in SDH activity, regulation, or mitochondria chaperones leading to succinate accumulation. Succinate plays a significant role in the growth of cancer through the production of epigenetic and metabolic changes as well as through its impact on angiogenesis, invasion, and cell migration. Therefore, there must be approaches that keep succinate from building up. Recently, flavonoids played an important role in SDH activity regulation. One of these is NAR, a substance that is naturally contained in many fruits. In clinical trials, the probability of serious side effects manifesting seems to be minimal, and it is anticipated to have a safer profile when compared to other chemotherapeutic drugs. However, the bioavailability and release of new formulations for encapsulating NAR like chitosan nanoparticles must also be further studied in relation to clinical trials, as to date the results of in vitro and in vivo models, opening the way for the development of new cancer therapies.
Thanks to the Biochemistry department, Faculty of Science Tanta University, Egypt.
RE: writing original draft preparation, designing all figures, and editing. GD: conceptualization. MT: supervision and investigation. KA: reviewing and editing. The authors read and approved the final manuscript.
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