**1. Introduction**

Human mitochondrial complex II (succinate:ubiquinone oxidoreductase; succinate dehydrogenase (SDH)) is an intriguing enzyme, which has been the focus of medical research during the past few decades since it contributes to pathogenesis of mitochondrial diseases (for recent reviews, see [1, 2]) and also a target for chemotherapy [3–5].

#### **1.1. Structure of mitochondrial complex II**

Mitochondrial complex II is a heterotetrameric protein embedded in the inner mitochondrial membrane. Its four subunits are referred as flavoprotein subunit (Fp), iron-sulfur subunit

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(Ip), cytochrome *b* large subunit (CybL), and cytochrome *b* small subunit (CybS). The Fp and Ip subunits comprise the catalytic domain of the enzyme. The Fp subunit has a flavin adenine dinucleotide (FAD) as a prosthetic group and contains the dicarboxylate-binding site, which serves as the binding site for succinate and fumarate. The Ip subunit generally contains three iron-sulfur clusters [2Fe-2S]2+,1+, [4Fe-4S]2+,1+, and [3Fe-4S]1+,0 as prosthetic groups. Subunits CybL and CybS, with heme *b* as the prosthetic group, form the anchor domain of the enzyme. This anchors the catalytic domain to the inner mitochondrial membrane and also forms the quinone (Q)-binding site, together with the Ip subunit [6, 7] (**Figure 1**).

**1.2. Function of mitochondrial complex II**

In human cells, this enzyme plays dual roles as an indispensable enzyme in the TCA cycle as well as in the aerobic respiratory chain (**Figure 2**). It oxidizes succinate to fumarate in the TCA cycle and reduces quinone to quinol in the aerobic respiratory chain [6, 12]. This is in contrast to the function of the mitochondrial complex II of the anaerobic organisms such as *Ascaris suum,* which oxidizes quinol into quinone that is coupled with reduction of fumarate to succinate (**Figure 3**) [13]. However, our laboratory has revealed distinct fumarate reductase (FRD) activity in the human cancer cells, which have significantly increased upon exposure to hypoxia and hypoglycemia. In these cells, mitochondrial complex II is reported to acquire FRD activity through phosphorylation of its Fp subunit [11]. This finding is further supported

Differential Effect of Atpenin A5 on ROS Production from Wild-Type Mitochondrial Complex II…

http://dx.doi.org/10.5772/intechopen.71638

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**Figure 2.** Schematic representation of the function of the mitochondrial complex II in the aerobic respiratory chain and the TCA cycle. Functioning as a component of the TCA cycle, mitochondrial complex II catalyzes the oxidation of succinate to fumarate with transfer of electrons to FAD. Functioning as a component of the aerobic respiratory chain, the electrons on FAD are transferred through Fe-S clusters and heme *b* to reduce the ubiquinone. For simplicity of the

representation, the subunit composition of the respiratory chain complexes I, III, IV, and V is not shown.

In 2003, our laboratory revealed that human mitochondrial complex II exists in two isoforms, which differ in the Fp subunit. These two human Fp subunits, which are referred as Fp I and Fp II, differ only in two amino acids in the C-terminal of the protein-Tyr629Phe and Val657Ile [8, 9]. The majority of human tissues have shown expression of both isoforms of complex II with predominant expression of type I Fp. However, some cancer cell lines and fetal tissues have shown predominant expression of type II Fp also [4]. Furthermore, type II Fp expression has been found to increase in cultured cells under ischemic conditions [10]. Moreover, our laboratory has revealed that Fp subunit of human complex II undergoes posttranslational modifications by phosphorylation of its tyrosine, threonine, and serine residues under tumor mimicking microenvironments (hypoxic and hypoglycemic conditions), which affects its enzymatic activity [11].

**Figure 1.** Schematic representation of the mitochondrial complex II. The four subunits of the complex II, namely the flavoprotein subunit, iron sulfur subunit, cytochrome *b* large subunit, and cytochrome *b* small subunit are labeled as Fp, Ip, CybL, and CybS, respectively. The prosthetic groups that participate in the electron transfer are the flavin adenine dinucleotide (FAD), three iron sulfur clusters 2Fe-2S, 3Fe-4S, 4Fe-4S, and heme *b*. Dicarboxylate-binding site in the Fp subunit serves as the catalytic site for succinate oxidation/fumarate reduction. Quinone-binding site comprised of Ip, CybL, and CybS subunits serves as the catalytic site for quinone reduction/quinol oxidation.
