Complex 2: Structure, Function, and Disease

Within our cells, mitochondria function as the primary powerhouses, generating the energy required for life. At the heart of this energy production is Complex II, a multi-protein assembly also called succinate dehydrogenase. It is a component of the cellular processes that convert nutrients into usable energy. Its function is integrated into two of the cell’s most important energy-producing pathways, and its proper operation is directly linked to metabolic health.

Architectural Blueprint of Complex II

Embedded within the inner mitochondrial membrane, Complex II has a four-part structure. This assembly consists of four protein subunits: SDHA, SDHB, SDHC, and SDHD. The SDHA and SDHB subunits extend into the mitochondrial matrix and are the catalytic core where primary chemical reactions take place. The other two subunits, SDHC and SDHD, serve as an anchor, embedding the entire structure into the inner mitochondrial membrane.

To facilitate its chemical activities, Complex II utilizes specialized non-protein components known as prosthetic groups. The SDHA subunit contains a molecule called Flavin Adenine Dinucleotide (FAD), which is directly involved in accepting electrons. The SDHB subunit houses a series of three iron-sulfur (Fe-S) clusters. These clusters form a chain, allowing electrons to be passed through the protein, similar to a wire conducting electricity.

The precise positioning of these subunits and their prosthetic groups creates a defined pathway for electron movement. The process begins at the SDHA subunit and continues through the iron-sulfur clusters in SDHB. The journey culminates where electrons are transferred to a mobile carrier molecule within the mitochondrial membrane, ensuring efficient energy transfer.

Complex II’s Central Role in Cellular Respiration

Complex II holds a unique position in cellular metabolism because it participates in two interconnected pathways: the Krebs cycle and the electron transport chain. This dual functionality distinguishes it from other respiratory complexes. In the Krebs cycle, a series of reactions that break down nutrients, Complex II acts as the enzyme succinate dehydrogenase.

In its enzymatic role, Complex II catalyzes the oxidation of succinate into fumarate. During this conversion, two electrons are released from succinate and captured by the FAD molecule in the SDHA subunit, forming FADH2. This step provides a direct link between the Krebs cycle in the mitochondrial matrix and the electron transport chain.

Once the electrons are secured by FAD, they are funneled into the electron transport chain. The electrons travel from FADH2 along the iron-sulfur clusters within the SDHB subunit to a mobile molecule called ubiquinone. Upon receiving the two electrons, ubiquinone is reduced to ubiquinol, which then shuttles the electrons to Complex III, continuing the energy-transfer process.

A defining characteristic of Complex II is that it does not pump protons across the inner mitochondrial membrane. Other complexes in the chain, specifically Complexes I, III, and IV, use energy from electron transfer to move protons from the matrix to the intermembrane space. This action creates a proton gradient that drives the synthesis of ATP. Because electrons entering via Complex II bypass the proton-pumping action of Complex I, they contribute less to the overall proton gradient and yield less ATP.

When Complex II Falters: Health Implications

Mutations in the genes SDHA, SDHB, SDHC, and SDHD can lead to a faulty or non-functional complex. These genetic defects are the cause of diseases known as Complex II deficiencies, which account for about 2% of diagnosed mitochondrial diseases. The consequences can manifest as severe neurological and muscular disorders, including conditions like Leigh syndrome and other forms of encephalomyopathy.

Beyond inherited mitochondrial diseases, mutations in Complex II genes are strongly associated with certain types of cancer. Deficiencies are linked to the development of paragangliomas and pheochromocytomas, which are tumors of the nervous system, as well as some gastrointestinal stromal tumors (GISTs) and kidney cancers. The connection arises because the malfunction disrupts cellular metabolism, which can create an environment that favors tumor growth.

A significant consequence of a malfunctioning Complex II is the increased production of reactive oxygen species (ROS). When electrons are not transferred efficiently to ubiquinone, they can leak out and react with oxygen to form damaging molecules. This leads to a state of oxidative stress, which can cause widespread damage to cellular components, including DNA, proteins, and lipids. This cellular damage is a contributing factor in both neurodegenerative diseases and the progression of cancer.