SDHB
Encyclopedia
Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial (SDHB) also known as iron-sulfur subunit of complex II (Ip) is a protein
that in humans is encoded by the SDHB gene
.
The succinate dehydrogenase (also called SDH or Complex II) protein complex catalyzes
the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). SDHB is one of four protein subunits forming succinate dehydrogenase, the other three being SDHA
, SDHC and SDHD
. The SDHB subunit is connected to the SDHA
subunit on the hydrophilic, catalytic end of the SDH complex. It is also connected to the SDHC/SDHD
subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. The subunit is an iron-sulfur protein
with three iron-sulfur clusters. It weighs 30 kDa
.
and Respiratory chain.
SDHB acts as an intermediate in the basic SDH enzyme action shown in Figure 1:
, not mitchondrial DNA
. However, the protein is located in the inner membrane of the mitochondria. The location of the gene in humans is on the first chromosome
at locus
p36.1-p35. The gene
is coded in 1162 base pairs, partitioned in 8 exon
s. The expressed protein has 280 amino acids.
mutations in the gene can cause familial paraganglioma
(in old nomenclature, Paraganglioma Type PGL4). The same condition is often called familial pheochromocytoma
. Less frequently, renal cell carcinoma
can be caused by this mutation.
Paragangliomas related to SDHB mutations have a high rate of malignancy. When malignant, treatment is currently the same as for any malignant paraganglioma/pheochromocytoma.
Mutations causing disease have been seen in exon
s 1 through 7, but not 8. As with the SDHC and SDHD
genes, SDHB is a tumor suppressor gene
. Note the SDHA
gene is not a tumor suppressor gene.
Tumor formation generally follows the Knudson "two hit"
hypothesis. The first copy of the gene is mutated in all cells, however the second copy functions normally. When the second copy mutates in a certain cell due to a random event, Loss of Heterozygosity (LOH)
occurs and the SDHB protein is no longer produced. Tumor formation then becomes possible.
Given the fundamental nature of the SDH protein in all cellular function, it is not currently understood why only paraganglionic cells are affected. However, the sensitivity of these cells to oxygen levels may play a role.
. The dashed red arrow in Figure 2 shows this. ROS accumulate and stabilize the production of HIF1-α. HIF1-α combines with HIF1-β to form the stable HIF heterodimeric complex, in turn leading to the induction of antiapoptotic
genes in the cell nucleus.
This pathway raises the possibility of a therapeutic treatment. The build-up of succinate inhibits PHD activity. PHD action normally requires oxygen and alpha-ketoglutarate as cosubstrates and ferrous iron and ascorbate
as cofactors
. Succinate competes with α-ketoglutarate in binding to the PHD enzyme. Therefore, increasing α-ketoglutarate levels can offset the effect of succinate accumulation.
Normal α-ketoglutarate does not permeate cell walls efficiently, and it is necessary to create a cell permeating derivative (e.g. α-ketoglutarate esters). In-vitro trials show this supplementation approach can reduce HIF1-α levels, and may result in a therapeutic approach to tumours resulting from SDH deficiency.
cells present in an embryo
. Abdominal extra-adrenal paraganglionic cells secrete catecholamines that play an important role in fetal development. After birth these cells usually die, a process that is triggered by a decline in nerve growth factor
(NGF)which initiates apoptosis
(cell death).
This cell death process is mediated by an enzyme called prolyl hydroxylase EglN3. Succinate accumulation caused by SDH inactivation inhibits the prolyl hydroxylase EglN3. The net result is that paranglionic tissue that would normally die after birth remains, and this tissue may be able to trigger paraganglioma/pheochromocytoma later.
glycolytically in order to generate its required energy. The induced glycolytic enzymes could potentially block cell apoptosis.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the SDHB gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
The succinate dehydrogenase (also called SDH or Complex II) protein complex catalyzes
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). SDHB is one of four protein subunits forming succinate dehydrogenase, the other three being SDHA
SDHA
Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHA gene.The succinate dehydrogenase protein complex catalyzes the oxidation of succinate . The SDHA subunit is connected to the SDHB subunit on the hydrophilic, catalytic end of the...
, SDHC and SDHD
SDHD
Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial , also known as succinate dehydrogenase complex subunit D , is a protein that in humans is encoded by the SDHD gene....
. The SDHB subunit is connected to the SDHA
SDHA
Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHA gene.The succinate dehydrogenase protein complex catalyzes the oxidation of succinate . The SDHA subunit is connected to the SDHB subunit on the hydrophilic, catalytic end of the...
subunit on the hydrophilic, catalytic end of the SDH complex. It is also connected to the SDHC/SDHD
SDHD
Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial , also known as succinate dehydrogenase complex subunit D , is a protein that in humans is encoded by the SDHD gene....
subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. The subunit is an iron-sulfur protein
Iron-sulfur protein
Iron-sulfur proteins are proteins characterized by the presence of iron-sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states...
with three iron-sulfur clusters. It weighs 30 kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
.
Function of the SDHB protein
The SDH complex is located on the inner membrane of the mitochondria and participates in both the Citric Acid CycleCitric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
and Respiratory chain.
SDHB acts as an intermediate in the basic SDH enzyme action shown in Figure 1:
- SDHASDHASuccinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHA gene.The succinate dehydrogenase protein complex catalyzes the oxidation of succinate . The SDHA subunit is connected to the SDHB subunit on the hydrophilic, catalytic end of the...
converts succinate to fumarate as part of the Citric Acid CycleCitric acid cycleThe citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
. This reaction also converts FADFADIn biochemistry, flavin adenine dinucleotide is a redox cofactor involved in several important reactions in metabolism. FAD can exist in two different redox states, which it converts between by accepting or donating electrons. The molecule consists of a riboflavin moiety bound to the phosphate...
to FADH2. - Electrons from the FADH2 are transferred to the SDHB subunit iron clustersIron-sulfur proteinIron-sulfur proteins are proteins characterized by the presence of iron-sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states...
[2Fe-2S],[4Fe-4S],[3Fe-4S]. - Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHDSDHDSuccinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial , also known as succinate dehydrogenase complex subunit D , is a protein that in humans is encoded by the SDHD gene....
subunits.This function is part of the Respiratory chain.
Gene that codes for SDHB
The gene that codes for the SDHB protein is nuclearNuclear DNA
Nuclear DNA, nuclear deoxyribonucleic acid , is DNA contained within a nucleus of eukaryotic organisms. In mammals and vertebrates, nuclear DNA encodes more of the genome than the mitochondrial DNA and is composed of information inherited from two parents, one male, and one female, rather than...
, not mitchondrial DNA
Mitochondrial DNA
Mitochondrial DNA is the DNA located in organelles called mitochondria, structures within eukaryotic cells that convert the chemical energy from food into a form that cells can use, adenosine triphosphate...
. However, the protein is located in the inner membrane of the mitochondria. The location of the gene in humans is on the first chromosome
Chromosome 1 (human)
Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 247 million nucleotide base pairs, which are the basic units of information for DNA...
at locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
p36.1-p35. The gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
is coded in 1162 base pairs, partitioned in 8 exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s. The expressed protein has 280 amino acids.
Role in Disease
GermlineGermline
In biology and genetics, the germline of a mature or developing individual is the line of germ cells that have genetic material that may be passed to a child.For example, gametes such as the sperm or the egg, are part of the germline...
mutations in the gene can cause familial paraganglioma
Paraganglioma
A paraganglioma is a rare neuroendocrine neoplasm that may develop at various body sites . About 97% are benign and cured by surgical removal; the remaining 3% are malignant because they are able to produce distant metastases...
(in old nomenclature, Paraganglioma Type PGL4). The same condition is often called familial pheochromocytoma
Pheochromocytoma
A pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
. Less frequently, renal cell carcinoma
Renal cell carcinoma
Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
can be caused by this mutation.
Paragangliomas related to SDHB mutations have a high rate of malignancy. When malignant, treatment is currently the same as for any malignant paraganglioma/pheochromocytoma.
Tumour and Disease Characteristics
Paragangliomas caused by SDHB mutations have several distinguishing characteristics:- Malignancy is common, ranging from 38%-83%in carriers with disease. In contrast, tumors caused by SDHDSDHDSuccinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial , also known as succinate dehydrogenase complex subunit D , is a protein that in humans is encoded by the SDHD gene....
mutations are almost always benign. Sporadic paragangliomas are malignant in less than 10% of cases. - Malignant paragangliomas caused by SDHB are usually (perhaps 92%) extra-adrenal. Sporadic pheochromocytomas/paragangliomas are extra-adrenal in less than 10% of cases.
- The penetrancePenetrancePenetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
of the gene is often reported as 77% by age 50 (i.e. 77% of carriers will have at least one tumour by the age of 50). This is likely an overestimate. Currently (2011), families with silent SDHB mutations are being screened to determine the frequency of silent carriers. - The average age of onset is approximately the same for SDHB vs non-SDHB related disease (approximately 36 years).
Mutations causing disease have been seen in exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s 1 through 7, but not 8. As with the SDHC and SDHD
SDHD
Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial , also known as succinate dehydrogenase complex subunit D , is a protein that in humans is encoded by the SDHD gene....
genes, SDHB is a tumor suppressor gene
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
. Note the SDHA
SDHA
Succinate dehydrogenase complex, subunit A, flavoprotein variant is a protein that in humans is encoded by the SDHA gene.The succinate dehydrogenase protein complex catalyzes the oxidation of succinate . The SDHA subunit is connected to the SDHB subunit on the hydrophilic, catalytic end of the...
gene is not a tumor suppressor gene.
Tumor formation generally follows the Knudson "two hit"
Knudson hypothesis
The Knudson hypothesis is the hypothesis that cancer is the result of accumulated mutations to a cell's DNA. It was first proposed by Carl O. Nordling in 1953, and later formulated by Alfred G. Knudson in 1971. Knudson's work led indirectly to the identification of cancer-related genes...
hypothesis. The first copy of the gene is mutated in all cells, however the second copy functions normally. When the second copy mutates in a certain cell due to a random event, Loss of Heterozygosity (LOH)
Loss of heterozygosity
Loss of heterozygosity in a cell is the loss of normal function of one allele of a gene in which the other allele was already inactivated. This term is mostly used in the context of oncogenesis; after an inactivating mutation in one allele of a tumor suppressor gene occurs in the parent's germline...
occurs and the SDHB protein is no longer produced. Tumor formation then becomes possible.
Given the fundamental nature of the SDH protein in all cellular function, it is not currently understood why only paraganglionic cells are affected. However, the sensitivity of these cells to oxygen levels may play a role.
Disease pathways
The precise pathway leading from SDHB mutation to tumorigenesis is not determined; there are several proposed mechanisms.Generation of reactive oxygen species
When succinate-ubiquinone activity is inhibited, electrons that would normally transfer through the SDHB subunit to the Ubiquinone pool are instead transferred to O2 to create Reactive Oxygen Species (ROS) such as superoxideSuperoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
. The dashed red arrow in Figure 2 shows this. ROS accumulate and stabilize the production of HIF1-α. HIF1-α combines with HIF1-β to form the stable HIF heterodimeric complex, in turn leading to the induction of antiapoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
genes in the cell nucleus.
Succinate accumulation in the cytosol
SDH inactivation can block the oxidation of succinate, starting a cascade of reactions:- The succinate accumulated in the mitochondrial matrix diffuses through the inner and outer mitochondrial membranes to the cytosolCytosolThe cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
(purple dashed arrows in Figure 2). - Under normal cellular function, HIF1-α in the cytosol is quickly hydroxylatedHydroxylationHydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...
by prolyl hydroxylaseProlyl hydroxylaseProlyl hydroxylase is an enzyme involved in the production of collagen, acting to hydroxylate proline to hydroxyproline....
(PHD), shown with the light blue arrow. This process is blocked by the accumulated succinate. - HIF1-α stabilizes and passes to the cell nucleus (orange arrow) where it combines with HIF1-β to form an active HIF complex that induces the expression of tumor causing genes.
This pathway raises the possibility of a therapeutic treatment. The build-up of succinate inhibits PHD activity. PHD action normally requires oxygen and alpha-ketoglutarate as cosubstrates and ferrous iron and ascorbate
Vitamin C
Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...
as cofactors
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
. Succinate competes with α-ketoglutarate in binding to the PHD enzyme. Therefore, increasing α-ketoglutarate levels can offset the effect of succinate accumulation.
Normal α-ketoglutarate does not permeate cell walls efficiently, and it is necessary to create a cell permeating derivative (e.g. α-ketoglutarate esters). In-vitro trials show this supplementation approach can reduce HIF1-α levels, and may result in a therapeutic approach to tumours resulting from SDH deficiency.
Impaired developmental apoptosis
Paraganglionic tissue is derived from the neural crestNeural crest
Neural crest cells are a transient, multipotent, migratory cell population unique to vertebrates that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia....
cells present in an embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
. Abdominal extra-adrenal paraganglionic cells secrete catecholamines that play an important role in fetal development. After birth these cells usually die, a process that is triggered by a decline in nerve growth factor
Nerve growth factor
Nerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons . It also functions as a signaling molecule. It is perhaps the prototypical growth factor, in that it is one of the first to be described...
(NGF)which initiates apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
(cell death).
This cell death process is mediated by an enzyme called prolyl hydroxylase EglN3. Succinate accumulation caused by SDH inactivation inhibits the prolyl hydroxylase EglN3. The net result is that paranglionic tissue that would normally die after birth remains, and this tissue may be able to trigger paraganglioma/pheochromocytoma later.
Glycolysis upregulation
Inhibition of the Citric Acid Cycle forces the cell to create ATPAdenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
glycolytically in order to generate its required energy. The induced glycolytic enzymes could potentially block cell apoptosis.