Succinate Dehydrogenase and Ribonucleic Acid Networks in Cancer and Other Diseases

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: RNA-editing; RNA-modification; cancer; disease; electron transport chain; metabolism; non-coding RNA; reactive oxygen species; succinate dehydrogenase; tricarboxylic acid cycle.

Figure 1

Structure, maturation, and assembly of succinate dehydrogenase (SDH) complex. The SDH complex, or mitochondrial complex II, sits within the inner mitochondrial membrane and is included 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 factors SDHAF1 and SDHAF2 assist in the maturation of subunits A and B. SDHAF1 provides Fe-S clusters to SDHB and SDHAF2 works in conjunction with dicarboxylate to stabilize the active site of SDHA. The next subunits, C and D, house heme and are responsible for ubiquinone reduction to ubiquinol. From here, ubiquinol is transferred to complex III of the ETC. The three known pseudogenes of SDHA, SDHAP1-3, are also included, whose metabolic function is still unknown.

Figure 2

Genetic and metabolic dysfunction of the SDH complex and its link to diseases. For instance, SDHB mutations lead to the development of paraganglioma (PGL), pheochromocytoma (PCC), ovarian cancer, colorectal cancer, gastrointestinal tumors (GISTs), and other cancers. Similarly, SDHB mutations can cause non-cancer diseases such as leukodystrophy and premature aging. Another way that abnormal SDH activity causes the disease is through its metabolic dysfunction, as seen with decreased activities of SDHA and SDHB through epigenetic modification causing acute mountain sickness.

Figure 3

A network of RNA regulators interacting with succinate dehydrogenase. Different proteins/processes affecting the transcription/translation of the SDH complex are shown. For example, the RNA-editing enzyme APOBEC3A decreases the expression of SDHB. Similarly, the non-coding RNAs miR-31 and miR-210 decrease SDHA and SDHD activity, respectively. It is important to note that the interplay between RNA-editing enzymes and RNA-modification genes with non-coding RNAs has been established, but the possible role of these regulators and their effect on SDH has yet to be discovered and warrants intrigue. Regulations are signified with inhibition (┤) and promotion (→) together with upregulation (red lettering) and downregulation (green lettering).

Figure 4

Strategies for Targeting Succinate Dehydrogenase Complex. Ubiquinone binding inhibitors carboxin, TTFA, and α-Tocopheryl succinate bind and deactivate SDH at the proximal Q_P and distal Q_D ubiquinone binding sites. Ubiquinone binding inhibitors disrupt the reduction of ubiquinone to ubiquinol, a key step in the ETC. Succinate binding inhibitors malonate, oxaloacetate, and malate bind at the catalytic core or succinate pocket of SDH. Succinate pocket inhibitors are typically intermediates from the TCA cycle that modulate SDH activity based on cellular needs. Genetic inhibitor TRAP1 is a mitochondrial chaperone that inhibits SDH functions causing hypoxic environments that stimulate tumorigenesis. SDH activators such as succinate, Rapamycin, and Naringin function as small molecules activators of SDH. Additionally, genetic activator SIRT3 regulates the deacetylation of SDHA. NRF1 is an oxygen-sensing protein that binds to SDH genetic promoters when there is a lack of oxygen to limit ETC energy production until suitable oxygen conditions are resumed.