What Does Succinate Dehydrogenase Do in Cell Metabolism?

Cells rely on intricate biochemical pathways to generate energy, and succinate dehydrogenase (SDH) plays a key role in this process. As an enzyme complex embedded in the inner mitochondrial membrane, SDH is unique because it functions in both the citric acid cycle and the electron transport chain, linking two essential metabolic processes.

Because of its central position in metabolism, disruptions in SDH activity can have significant consequences. Mutations in SDH subunits are linked to various health conditions, including certain cancers and neurodegenerative diseases. Understanding SDH provides insight into both normal cellular function and disease mechanisms.

Role in the Electron Transport Chain

Succinate dehydrogenase (SDH) is the only enzyme that participates in both the citric acid cycle and the electron transport chain (ETC). Within the ETC, SDH, also known as Complex II, transfers electrons from succinate to ubiquinone (coenzyme Q), contributing to oxidative phosphorylation, the process by which cells generate ATP. Unlike Complex I, which receives electrons from NADH, Complex II provides an alternative entry point for electrons, ensuring metabolic flexibility.

The oxidation of succinate to fumarate releases two electrons, which are accepted by flavin adenine dinucleotide (FAD), a tightly bound prosthetic group within SDH. The reduction of FAD to FADH₂ enables electron transfer through iron-sulfur (Fe-S) clusters, including [2Fe-2S], [4Fe-4S], and [3Fe-4S] centers. These clusters guide electrons toward ubiquinone, reducing it to ubiquinol, which then moves to Complex III, continuing the electron transport process.

Unlike Complex I, Complex II does not contribute to proton pumping across the inner mitochondrial membrane, meaning electrons entering the ETC via SDH generate slightly less ATP than those from NADH oxidation. However, SDH plays a crucial role in linking the citric acid cycle with the ETC, regulating metabolic flux and ensuring efficient processing of intermediates. Additionally, SDH activity influences reactive oxygen species (ROS) production, as electron leakage from the enzyme can contribute to oxidative stress and mitochondrial dysfunction.

Function in the Citric Acid Cycle

Succinate dehydrogenase (SDH) catalyzes the oxidation of succinate to fumarate, progressing the citric acid cycle while generating reducing equivalents for cellular respiration. This reaction, unique within the cycle, directly links to the electron transport chain. The oxidation of succinate is coupled with the reduction of FAD to FADH₂, facilitating electron movement and reinforcing SDH’s dual role in metabolism.

The conversion of succinate to fumarate is an exergonic reaction, occurring spontaneously under physiological conditions and driving the turnover of citric acid cycle intermediates. SDH’s active site binds succinate, positioning it for oxidation. As succinate dehydrogenates, two hydrogen atoms transfer to FAD, forming FADH₂, which donates electrons to the mitochondrial electron transport chain via iron-sulfur clusters. The resulting fumarate proceeds to the next step, hydrated to malate by fumarase.

SDH activity influences metabolic flux by responding to substrate availability and energy demands. When ATP levels are high, feedback mechanisms slow succinate oxidation, conserving intermediates for biosynthesis. During increased energy expenditure, SDH accelerates fumarate production and electron transfer to sustain ATP synthesis. This regulation ensures energy production remains balanced, preventing metabolic disruptions.

Structural Subunits

Succinate dehydrogenase (SDH) is a multi-subunit enzyme composed of SDHA, SDHB, SDHC, and SDHD, each with specialized functions. SDHA and SDHB form the catalytic core, while SDHC and SDHD anchor the complex to the inner mitochondrial membrane and participate in electron transport.

SDHA

SDHA is the catalytic subunit responsible for succinate oxidation. It contains a covalently bound FAD cofactor, which acts as the initial electron acceptor. As succinate binds to SDHA, two hydrogen atoms transfer to FAD, reducing it to FADH₂. These electrons then pass to iron-sulfur clusters in SDHB.

SDHA activity is regulated through post-translational modifications, such as phosphorylation, which influences metabolic flux. Mutations in SDHA are linked to metabolic disorders, including Leigh syndrome, a severe neurological condition, and certain cancers like gastrointestinal stromal tumors (GISTs).

SDHB

SDHB facilitates electron transfer from FADH₂ to ubiquinone via iron-sulfur (Fe-S) clusters, including [2Fe-2S], [4Fe-4S], and [3Fe-4S]. These clusters ensure efficient electron transport with minimal energy loss, preserving oxidative phosphorylation efficiency and reducing ROS formation.

Mutations in SDHB are strongly associated with hereditary paragangliomas and pheochromocytomas—tumors arising from neuroendocrine tissues. SDHB mutations are often linked to more aggressive tumor behavior and a higher likelihood of metastasis, emphasizing its importance in mitochondrial integrity and metabolic regulation.

SDHC

SDHC anchors the SDH complex within the inner mitochondrial membrane and plays a structural role in stabilizing the enzyme. It contains a heme b cofactor that participates in electron transfer, acting as an intermediary between SDHB’s iron-sulfur clusters and ubiquinone. This heme group helps regulate electron flow and prevents excessive electron leakage, which could lead to oxidative stress.

Mutations in SDHC are associated with hereditary paragangliomas and pheochromocytomas, though tumors linked to SDHC mutations tend to be less aggressive than those associated with SDHB. SDHC mutations have also been implicated in mitochondrial dysfunction syndromes, further highlighting its role in cellular metabolism.

SDHD

SDHD, another membrane-anchoring subunit, works with SDHC to stabilize the SDH complex and facilitate electron transfer to ubiquinone. Like SDHC, SDHD contains a heme b cofactor that regulates electron flow, ensuring efficient energy production and minimizing ROS generation.

Mutations in SDHD are associated with hereditary paragangliomas and pheochromocytomas, often exhibiting a parent-of-origin effect, where tumors predominantly develop when the mutation is inherited from the father. SDHD mutations are also linked to mitochondrial dysfunction and altered metabolic signaling, emphasizing its role in maintaining cellular homeostasis.

Associations With Certain Health Conditions

Disruptions in succinate dehydrogenase (SDH) function are implicated in various metabolic and tumor-related disorders. One of the most well-documented associations is with hereditary paragangliomas and pheochromocytomas, neuroendocrine tumors linked to SDH subunit mutations. These mutations cause succinate accumulation, which interferes with cellular signaling by inhibiting prolyl hydroxylases. This stabilizes hypoxia-inducible factors (HIFs), creating a pseudo-hypoxic state that promotes tumorigenesis through increased angiogenesis and metabolic reprogramming.

Beyond endocrine tumors, SDH mutations play a role in gastrointestinal stromal tumors (GISTs), particularly in cases lacking mutations in the KIT and PDGFRA oncogenes. SDH-deficient GISTs exhibit distinct molecular characteristics, often occurring in younger patients and demonstrating resistance to standard tyrosine kinase inhibitor therapies. Research into alternative treatments, including metabolic-targeting strategies, aims to counteract the effects of succinate accumulation.