SDHB is an acronym for
succinate dehydrogenase complex subunit B.
The term SDHB can refer to:
- The protein subunit itself.
- The gene that codes for this protein.
The succinate dehydrogenase (also called SDH or Complex II) protein complex
catalyzesCatalysis is the process in which the rate of a chemical reaction is either increased or decreased by means of a chemical substance known as a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. The catalyst may participate...
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
SDHASDHA is an acronym for succinate dehydrogenase complex subunit A.The term SDHA can refer to;* The protein subunit itself.* The gene that codes for this protein....
subunit on the hydrophilic, catalytic end of the SDH complex. It is also connected to the
SDHCSDHC or sdhc may refer to:* Secure Digital High-Capacity, a type of flash memory card* Succinate dehydrogenase complex subunit C, the gene* School District of Hillsborough County...
/
SDHDSDHD, which stands for succinate dehydrogenase complex subunit D, is one of the two transmembrane subunits of the four-subunit succinate dehydrogenase protein complex that resides in the inner mitochondrial membrane. It also refers to the gene that codes for this protein. The other transmembrane...
subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. The subunit is an
iron-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...
with three iron-sulfur clusters. It weighs 30
kDaThe unified atomic mass unit or atomic mass unit , or dalton or, sometimes, universal mass unit , is a unit of mass used to express atomic and molecular masses...
.
Function of the SDHB protein
The SDH complex is located on the inner membrane of the mitochondria and participates in both the
Citric Acid CycleThe citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or more rarely, the Szent-Györgyi-Krebs cycle — is a series of enzyme-catalysed chemical reactions, which is of central importance in all living cells that use oxygen as part of cellular respiration...
and Respiratory chain.
SDHB acts as an intermediate in the basic SDH enzyme action shown in Figure 1:
- SDHA
SDHA is an acronym for succinate dehydrogenase complex subunit A.The term SDHA can refer to;* The protein subunit itself.* The gene that codes for this protein....
converts succinate to fumarate as part of the Citric Acid CycleThe citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or more rarely, the Szent-Györgyi-Krebs cycle — is a series of enzyme-catalysed chemical reactions, which is of central importance in all living cells that use oxygen as part of cellular respiration...
. This reaction also converts FADIn biochemistry, flavin adenine dinucleotide is a redox cofactor involved in several important reactions in metabolism. FAD can exist in two different redox states and its biochemical role usually involves changing between these two states...
to FADH2.
- Electrons from the FADH2 are transferred to the SDHB subunit iron clusters
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...
[2Fe-2S],[4Fe-4S],[3Fe-4S].
- Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC
SDHC or sdhc may refer to:* Secure Digital High-Capacity, a type of flash memory card* Succinate dehydrogenase complex subunit C, the gene* School District of Hillsborough County...
/SDHDSDHD, which stands for succinate dehydrogenase complex subunit D, is one of the two transmembrane subunits of the four-subunit succinate dehydrogenase protein complex that resides in the inner mitochondrial membrane. It also refers to the gene that codes for this protein. The other transmembrane...
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 deoxyribonucleic acid , is DNA contained within a nucleus of eukaryotic organisms. In most cases it encodes more of the genome than the mitochondrial DNA and is passed sexually rather than matrilineally. Nuclear DNA is the most common DNA used in forensic examinations....
, not
mitchondrial DNAMitochondrial DNA is the DNA located in organelles called mitochondria, structures within cells that convert the energy from food into a form that cells can use...
. However, the protein is located in the inner membrane of the mitochondria. The location of the gene in humans is on the
first chromosomeChromosome 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
locusIn the fields of genetics and evolutionary 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
geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
is coded in 1162 base pairs, partitioned in 8
exonAn exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule after either portions of a precursor RNA have been removed by cis-splicing or by two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA or...
s.
The expressed protein has 280 amino acids.
Role in Disease
GermlineIn 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, sex cells such as the sperm or the egg, are part of the germline...
mutations in the gene can cause familial
paragangliomaA 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
pheochromocytomaA phaeochromocytoma or pheochromocytoma, 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 adrenaline and noradrenaline...
. Less frequently,
renal cell carcinomaRenal 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.
Paraganlgiomas 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 SDHD
SDHD, which stands for succinate dehydrogenase complex subunit D, is one of the two transmembrane subunits of the four-subunit succinate dehydrogenase protein complex that resides in the inner mitochondrial membrane. It also refers to the gene that codes for this protein. The other transmembrane...
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 penetrance
Penetrance is a term used in genetics to describe the proportion of individuals carrying a particular variation 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...
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 (2009), 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
exonAn exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule after either portions of a precursor RNA have been removed by cis-splicing or by two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA or...
s 1 through 7, but not 8. As with the
SDHCSDHC or sdhc may refer to:* Secure Digital High-Capacity, a type of flash memory card* Succinate dehydrogenase complex subunit C, the gene* School District of Hillsborough County...
and
SDHDSDHD, which stands for succinate dehydrogenase complex subunit D, is one of the two transmembrane subunits of the four-subunit succinate dehydrogenase protein complex that resides in the inner mitochondrial membrane. It also refers to the gene that codes for this protein. The other transmembrane...
genes, SDHB is a
tumor suppressor geneA tumor suppressor gene, or antioncogene, 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
SDHASDHA is an acronym for succinate dehydrogenase complex subunit A.The term SDHA can refer to;* The protein subunit itself.* The gene that codes for this protein....
gene is not a tumor suppressor gene.
Tumor formation generally follows the Knudson
"two hit"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 in a cell represents the loss of normal function of one allele of a gene in which the other allele was already inactivated...
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.
Pathway 1: 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 O
2 to create Reactive Oxygen Species (ROS) such as
superoxideSuperoxide is an anion with the chemical formula O
2−. It is important as the product of the one-electron reduction of dioxygen O
2, 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
antiapoptoticApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
genes in the cell nucleus.
Pathway 2: 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 cytosol
The cytosol or intracellular fluid is the liquid found inside cells. In eukaryotes this liquid is separated by cell membranes from the contents of the organelles suspended in the cytosol, such as the mitochondrial matrix inside the mitochondrion...
(purple dashed arrows in Figure 2).
- Under normal cellular function,HIF1-α in the cytosol is quickly hydroxylated
Hydroxylation is any chemical process that introduces one or more hydroxyl groups into a compound thereby oxidizing it. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases....
by prolyl hydroxylaseProlyl hydroxylase is an enzyme involved in the production of collagen, acting to hydroxylate proline to hydroxyproline.It requires vitamin C as a cofactor....
(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
ascorbateVitamin C or L-ascorbic acid is an essential nutrient for humans, in which it functions as a vitamin. Ascorbate is required for a range of essential metabolic reactions in all animals and plants...
as
cofactorsA 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/ions" 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.
Pathway 3: Impaired Developmental Apoptosis
Paraganglionic tissue is derived from the
neural crestThe neural crest, a transient component of the ectoderm, is located in between the neural tube and the epidermis of an embryo during neural tube formation...
cells present in an
embryoAn 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 factorNerve growth factor , is a small secreted protein which induces the differentiation and survival of particular target neurons...
(NGF)which initiates
apoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
(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.
Pathway 4: Glycolysis upregulation
Inhibition of the Citric Acid Cycle forces the cell to create
ATPAdenosine-5'-triphosphate is a multifunctional nucleotide that plays an important role in cell biology as a coenzyme, that is, 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.
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