Succinate dehydrogenase complex assembly factor 1 (SDHAF1), also known as LYR motif-containing protein 8 (LYRM8), is a protein that in humans is encoded by the ''SDHAF1,'' or ''LYRM8,'' gene. SDHAF1 is a chaperone protein involved in the assembly of the

succinate dehydrogenase Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates i ...

(SDH) complex ( complex II). Mutations in this gene are associated with SDH-defective infantile leukoencephalopathy and mitochondrial complex II deficiency.

Structure

''SDHAF1'' is located on the q arm of chromosome 19 in position 13.12 and has 1

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

. The ''SDHAF1'' gene produces a 12.8 kDa protein composed of 115 amino acids. ''SDHAF1'' is ubiquitously expressed and belongs to the complex I LYR family and SDHAF1 subfamily. As such, SDHAF1 is one of at least eight proteins that has a LYR tripeptide motif, thought to be important for Fe-S metabolism. ''SDHAF1'' also contains an

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

mitochondrial targeting sequence that does not get cleaved following import into the mitochondria. The encoded protein is fairly hydrophilic and does not contain a transmembrane domain.

Function

SDHAF1 is essential for the assembly of the

(SDH) complex ( complex II), an enzyme complex that is a component of both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain, and which couples the oxidation of succinate to

fumarate Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297. The salts and esters are known as f ...

with the reduction of ubiquinone (coenzyme Q) to ubiquinol. The succinate dehydrogenase (SDH) complex of the mitochondrial respiratory chain is composed of 4 individual subunits. The protein encoded by the ''SDHAF1'' gene resides in the

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

, and is essential for SDH assembly, but does not physically associate with the complex in vivo. Specifically, SDHAF1 mediates and promotes the maturation of the SDHB subunit of the SDH catalytic dimer. The iron-sulfur (Fe-S) protein subunit SDHB is required for functional succinate dehydrogenase. By protecting SDHB from damaging oxidants, SDHAF1 plays a vital role in the assembly and stability of succinate dehydrogenase (SDH). Alternatively, SDHAF1 may facilitate Fe-S cluster acquisition by SDHB by directly binding to the co-chaperone HSC20, which is an essential component of the Fe-S biogenesis machinery that facilitates transfer of the Fe-S prosthetic group from the main scaffold protein ISCU to recipient apo-proteins (i.e. SDHB),

Clinical Significance

Variants of ''SDHAF1'' have been associated with mitochondrial complex II deficiency and infantile leukoencephalopathy. Mitochondrial complex II deficiency is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations. Clinical features include psychomotor regression in infants, poor growth with lack of speech development, severe spastic quadriplegia,

dystonia Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often inten ...

, progressive leukoencephalopathy, muscle weakness, exercise intolerance, and

cardiomyopathy Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

. Some patients manifest Leigh syndrome or Kearns-Sayre syndrome. Missense mutations c.164 G > C, p.Arg55Pro and c.170 G > A, p.Gly57Glu, homozygous transversion 169G-C, p. Gly57-Arg, homozygous non sense mutation c.103G>T (p.Glu35X), and homozygous nonsense mutation c.22C > T, p.Gln8X have been associated with mitochondrial complex II deficiency due to SDHAF1 disfunction.

Interactions

SDHAF1 has 27 protein-protein interactions with 15 of them being co-complex interactions. HSCB, SDHB, ccdc136, KRT27,

CIDEB Cell death-inducing DFFA-like effector b, also known as ''CIDEB'', is a human gene. In humans, individuals carrying rare loss of function mutations in the ''CIDEB'' gene are protected against different aetiologies of liver disease. CIDEB Knockou ...

, HSPA9, and

ISCU Iron-sulfur cluster assembly enzyme ISCU, mitochondrial is a protein that in humans is encoded by the ''ISCU'' gene. It encodes an iron-sulfur (Fe-S) cluster scaffold protein involved in 2Fe-2S">2Fe-2S_cluster.html" ;"title="nowiki/>2Fe-2S clus ...

have all been found to interact with SDHAF1.

Structure

Function

Clinical Significance

Interactions

References

Further reading