cancers Review Succinate Dehydrogenase and Ribonucleic Acid Networks in Cancer and Other Diseases Cerena Moreno y , Ruben Mercado Santos y , Robert Burns y and Wen Cai Zhang * Department of Cancer Division, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd, Orlando, FL 32827, USA; [email protected] (C.M.); [email protected] (R.M.S.); [email protected] (R.B.) * Correspondence: [email protected]; Tel.: +14-(07)-2667178 These authors contributed equally to this work. y Received: 25 September 2020; Accepted: 30 October 2020; Published: 3 November 2020 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. Our review highlights that non-coding ribonucleic acids (RNAs), RNA editing enzymes, and RNA modifying enzymes regulate expressions and functions of the succinate dehydrogenase complex. This research will provide new strategies for treating succinate dehydrogenase-relevant diseases in a clinic. Abstract: Succinate dehydrogenase (SDH) complex connects both the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) in the mitochondria. However, SDH mutation or dysfunction-induced succinate accumulation results in multiple cancers and non-cancer diseases. The mechanistic studies show that succinate activates hypoxia response and other signal pathways via binding to 2-oxoglutarate-dependent oxygenases and succinate receptors. Recently, the increasing knowledge of ribonucleic acid (RNA) networks, including non-coding RNAs, RNA editors, and RNA modifiers has expanded our understanding of the interplay between SDH and RNA networks in cancer and other diseases. Here, we summarize recent discoveries in the RNA networks and their connections to SDH. Additionally, we discuss current therapeutics targeting SDH in both pre-clinical and clinical trials. Thus, we propose a new model of SDH–RNA network interaction and bring promising RNA therapeutics against SDH-relevant cancer and other diseases. Keywords: succinate dehydrogenase; cancer; disease; tricarboxylic acid cycle; electron transport chain; metabolism; reactive oxygen species; non-coding RNA; RNA-editing; RNA-modification 1. 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). The yme works by catalyzing succinate to fumarate by oxidation in the TCA cycle, then ubiquinone is reduced to ubiquinol in the ETC [1]. As a part of the TCA cycle, SDH gains electrons and transfers them through the four subunits (SDHA, SDHB, SDHC, SDHD) and continues this electron transfer through the ETC as complex II. The electrons from FADH2 and reduced ubiquinone are transferred to complex III to continue the production of adenosine triphosphate. This produces the energy for the cell. With the regulation of this enzyme through its various complexes, the cells are able to perform cellular respiration, hypoxic response, and other cellular activities such as gene expression. However, altered SDH activity could give rise to disease and cancer development due to reduced electron flow, increased oxygen toxicity, and accumulated succinate. Due to the various subunits within the SDH complex, the difference Cancers 2020, 12, 3237; doi:10.3390/cancers12113237 www.mdpi.com/journal/cancers Cancers 2020, 12, 3237 2 of 24 Cancers 2020, 12, x FOR PEER REVIEW 2 of 24 inchanges. functionality In some can behuman responsible cancer for cells, these SDH metabolic demonstrates changes. tumor-suppre In some humanssive cancer properties cells, SDH by demonstratesinactivating hypoxia-inducible tumor-suppressive factor properties 1α (HIF-1 by inactivatingα) via reduced hypoxia-inducible succinate [2]. factor Additionally, 1α (HIF-1α) viathe reducedsubunits succinateof SDH can [2 ].intera Additionally,ct with ribonucleic the subunits acid of(RNA) SDH regulatory can interact networks with ribonucleic including acidnon-coding (RNA) regulatoryRNAs, RNA-editing networks includingenzymes, RNA-modifying non-coding RNAs, enzymes, RNA-editing transcription enzymes, factors, RNA-modifying and small molecules. enzymes, transcriptionA consequence factors, of RNA and modifications small molecules. and A deregulation consequence of of non-coding RNA modifications RNAs is andthe deregulationability to act ofas non-codingtumor suppressors RNAsis or the oncogenes ability to and act alter as tumor gene suppressorsexpression, dysregulate or oncogenes cell and signaling alter gene pathways, expression, and dysregulatealter cell metabolism cell signaling [3,4]. pathways, Among them, and non-coding alter cell metabolism RNAs can [ 3target,4]. 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Here, physiological we summarize and thepathological SDH-relevant mechanisms physiological as well and as diseases pathological including mechanisms cancer. asAdditionally, well as diseases we discuss including innovative cancer. Additionally,ways that RNA we discussnetworks innovative influence ways SDH thatstate RNA and networks promising influence strategies SDH for state targeting and promising the SDH strategiescomplex. for targeting the SDH complex. 2.2. Succinate Dehydrogenase-AssociatedDehydrogenase-Associated GenesGenes andand ProteinProtein StructuresStructures 2.1.2.1. SDH Complex-Associated Genes TheThe SDHSDH complexcomplex isis composed composed of of four four subunits subunits that that are are encoded encoded through through nuclear nuclear genes: genes: SDHA-D SDHA- inD mammals,in mammals, SDH1-4 SDH1-4 in yeast, in yeast, and SDH1-8and SDH1-8 in plants in (Figureplants 1(Figure). Each 1). subunit Each ofsubunit the complex of the functions complex throughfunctions assembly through genes assembly including genesSDHAF1, including SDHAF2, SDHAF1, SDHAF3 SDHAF2,, and SDHAF3SDHAF4, andor SDH5, SDHAF4 SDH6, or SDH5, SDH7, andSDH6,SDH8 SDH7,in yeast. and SDH8SDHAF2 in yeast.is an importantSDHAF2 is assembly an important factor assembly of flavination factor of of SDHA, flavination needed of SDHA, for the SDHneeded complex for the to SDH be functional. complex toSDHAF2 be functional.works SDHAF2 in conjunction works within conjunction dicarboxylates with dicarboxylates of the TCA cycle of bythe stabilizing TCA cycle theby stabilizing active site ofthe SDHA active[ site9]. SDHAF1of SDHAprovides [9]. SDHAF1 iron-sulfur provides (Fe-S) iron-sulfur clusters (Fe-S) for SDHB clusters by firstfor SDHB binding by then first recruitingbinding then the recruiting iron-sulfur the cluster iron-sulfur co-chaperone cluster proteinco-chapero HscBne (HSC20) protein [HscB10]. SDHAP1, (HSC20) SDHAP2,[10]. SDHAP1,and SDHAP3 SDHAP2,are and pseudogenes SDHAP3 are that pseudogenes are a partof that the are SDHA a part complex of the SDHA (refer tocomplex GeneCards). (refer Recently,to GeneCards). it was Recently, found that it was lncRNA found SDHAP1 that lncRNA upregulated SDHAP1 the upregulated expression the of expression EIF4G2 by of reducing EIF4G2 miR-4465by reducing levels miR-4465 in ovarian levels cancer in ovarian cells [11 cancer]. This cells suggests [11]. This that thesuggests pseudogenes that the maypseudogenes regulate genemay expressionsregulate gene through expressions sponging through microRNAs sponging [12 ].mi FurthercroRNAs study [12]. of Further regulation study by SDHAP1-3of regulationin theby SDHSDHAP1-3 complex in couldthe SDH be beneficial complex forcould understanding be beneficial the for functions understanding of the SDH the complex functions that of isthe beyond SDH metaboliccomplex that reactions. is beyond metabolic reactions. FigureFigure 1.1. Structure, maturation,maturation, andand assemblyassembly ofof succinatesuccinate dehydrogenasedehydrogenase (SDH)(SDH) complex.complex. TheThe SDHSDH complex,complex, oror mitochondrialmitochondrial complex complex II, II, sits sits within within the the inner inner mitochondrial mitochondrial membrane membrane and and is includedis included in in both the tricarboxylic acid cycle (TCA) and the electron transport chain (ETC). Succinate is an enzyme that is a part of the TCA cycle and is oxidized to fumarate through SDH; this is also present in the reverse reaction. From the oxidization, two electrons are transferred to subunit A to protonate FAD to FADH2 and release two electrons to the Fe-S clusters housed within subunit B. Assembly