Succinic dehydrogenase, or SDH, is an enzyme complex located in the inner mitochondrial membrane of eukaryotic cells where it functions in cellular energy production. This enzyme is found in all aerobic cells, from bacteria to mammals, highlighting its importance in life that relies on oxygen. Its presence within mitochondria, the cell’s powerhouses, is directly linked to the efficient generation of cellular energy.
The Dual Function of Succinic Dehydrogenase in Cellular Respiration
Succinic dehydrogenase is the only enzyme that participates in both the citric acid cycle and the electron transport chain. These two pathways are the core components of aerobic respiration, where cells convert nutrients into ATP, the cell’s main energy currency. SDH’s dual role creates a direct physical and functional link between these two systems.
Within the citric acid cycle, SDH oxidizes a molecule called succinate into fumarate, removing two hydrogen atoms. These atoms are captured by flavin adenine dinucleotide (FAD), which is bound to the SDH enzyme. This reaction is one of eight steps in the pathway that breaks down acetyl-CoA to release stored energy.
Simultaneously, SDH acts as Complex II in the mitochondrial electron transport chain. The enzyme transfers electrons from succinate to a mobile carrier in the mitochondrial membrane called ubiquinone (coenzyme Q). This transfer is a step in the chain of reactions where electrons are passed between protein complexes, driving the production of most of the cell’s ATP through oxidative phosphorylation.
Genetic Blueprint and Assembly of Succinic Dehydrogenase
The succinic dehydrogenase enzyme is a complex built from four protein subunits, each encoded by a specific gene: SDHA, SDHB, SDHC, and SDHD. These genes provide the instructions for building the components that must assemble correctly for the enzyme to function.
The SDHA subunit contains the binding site for succinate and the FAD cofactor, making it the catalytic core for the citric acid cycle reaction. The SDHB subunit contains iron-sulfur clusters that pass electrons from SDHA to the next part of the chain. Together, SDHA and SDHB form the catalytic portion of the enzyme.
The SDHC and SDHD subunits anchor the complex into the inner mitochondrial membrane, which is necessary for interacting with ubiquinone. Proper assembly also requires assistance from proteins known as assembly factors, encoded by genes like SDHAF1 and SDHAF2. Errors in any of these genes can lead to a dysfunctional enzyme.
Succinic Dehydrogenase Malfunctions and Disease Links
Mutations in the SDH genes can lead to hereditary cancer syndromes. A malfunctioning SDH cannot efficiently convert succinate to fumarate, causing a significant buildup of succinate within the cell. This accumulation is a primary driver of disease, turning the metabolite into an oncometabolite.
Excess succinate disrupts cellular signaling by inhibiting a class of oxygen-requiring enzymes. This leads to the stabilization of a protein called hypoxia-inducible factor 1-alpha (HIF-1α). HIF-1α is normally stable only in low-oxygen (hypoxic) conditions, where it promotes new blood vessel growth (angiogenesis) and a switch to anaerobic metabolism. The succinate-induced stabilization of HIF-1α creates a “pseudo-hypoxic” state that promotes tumor growth, which is why SDH is considered a tumor suppressor.
Defects in different SDH subunit genes are linked to specific cancers. Mutations in SDHB, SDHC, and SDHD are associated with a predisposition to paragangliomas (PGL) and pheochromocytomas (PCC), which are tumors of the neuroendocrine system. These tumors are often highly vascular due to HIF-1α-driven angiogenesis. These mutations also increase the risk for gastrointestinal stromal tumors (GIST) and certain types of renal cell carcinoma.
While most SDH-related diseases involve tumors, mutations in the SDHA gene can cause metabolic disorders in childhood. Because the SDHA subunit is the catalytic core, mutations in both copies of the gene (bi-allelic mutations) can lead to a profound loss of function. This results in mitochondrial complex II deficiency, manifesting as neurological conditions like Leigh syndrome, an encephalomyopathy affecting the central nervous system, as well as cardiomyopathy and optic atrophy. These conditions appear in energy-hungry tissues like the brain and muscle.