Mitochondrial import inner membrane translocase subunit TIM50 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''TIMM50''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Tim50 is a subunit of the Tim23 translocase complex in the inner mitochondrial membrane. Mutations in ''TIMM50'' can lead to

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

, severe intellectual disability, and

3-methylglutaconic aciduria 3-Methylglutaconic aciduria (MGA) is any of at least five metabolic disorders that impair the body's ability to make energy in the mitochondria. As a result of this impairment, 3-methylglutaconic acid and 3-methylglutaric acid build up and can be ...

. ''TIMM50'' expression is increased in breast cancer cells and decreased in hypertrophic hearts.

Structure

The ''TIMM50'' gene is located on the q arm of

chromosome 19 Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 61.7 million base pairs, the building material of DNA. It is considered the most Gene density, gene-ri ...

in position 13.2 and spans 13,373 base pairs. The gene produces a 39.6 kDa protein composed of 353

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

. This gene encodes a subunit of the TIM23 inner mitochondrial membrane translocase complex, which mediates the translocation of transit peptide-containing proteins across the

mitochondrial inner membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...

Function

The Tim50 protein functions as the receptor subunit that recognizes the mitochondrial targeting signal, or presequence, on protein cargo that is destined for the mitochondrial inner membrane and

matrix Matrix (: matrices or matrixes) or MATRIX may refer to: Science and mathematics * Matrix (mathematics), a rectangular array of numbers, symbols or expressions * Matrix (logic), part of a formula in prenex normal form * Matrix (biology), the m ...

. Knockdown of this gene in human cells results in the release of cytochrome c and

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

. This protein plays a role in maintaining the membrane permeability barrier. The

intermembrane space The intermembrane space (IMS) is the space occurring between or involving two or more membranes. In cell biology, it is most commonly described as the region between the Inner mitochondrial membrane, inner membrane and the Outer mitochondrial memb ...

domain of Tim50 induces the translocation pore of the TIM23 channel to close.

Clinical significance

Missense mutations in ''TIMM50'' often result in epilepsy or epileptic

encephalopathy Encephalopathy (; ) means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome ...

, severe intellectual disability, variable mitochondrial complex V deficiency, and 3-methylglutaconic aciduria, which is a key biomarker for mitochondrial membrane defects and mitochondrial dysfunction. Inheritance of ''TIMM50'' is

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

. Expression of the TIMM50 gene is increased in

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

cells. In such cells, overexpression of the Tim50 protein is linked to lack of cellular apoptosis and increased rates of proliferation. Decreased ''TIMM50'' expression in heart cells can lead to cardiac

hypertrophy Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number. Although hypertro ...

. Two patients, male and female siblings born to consanguineous Bedouin parents were presented, displaying involuntary abnormal movements, failure to thrive, hypsarrhythmia, bilateral optic atrophy, 3-methylglutaconic aciduria, and slightly elevated plasma lactate levels. Both began walking independently at only 3 years and initially received favorably

ACTH Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...

therapy until switching to a treatment of

Valproate Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with ...

with either Sabril or

Topamax Topiramate, sold under the brand name Topamax among others, is a medication used to treat epilepsy and prevent migraines. It has also been used for alcohol dependence and essential tremor. For epilepsy, this includes treatment for generali ...

, which resulted in seizures completely disappearing. Two more patients, male and female siblings born to first-cousin parents of Muslim origin were also presented, displaying myoclonic and tonic seizures, abnormal

EEG Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The bio signals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neoc ...

, brain atrophy, delayed psychomotor development and 3-methylglutaconic aciduria. Treatment of

Lamictal Lamotrigine ( ), sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut ...

combined with Valproate was effective in controlling the seizures.

Interactions

Within the TIM23 complex, the Tim50 subunit directly interacts with ''TIMM23''. The TIM23 complex interacts with the ''

TIMM44 Mitochondrial import inner membrane translocase subunit TIM44 is an enzyme that in humans is encoded by the ''TIMM44'' gene. Interactions TIMM44 has been shown to interact with ARAF Serine/threonine-protein kinase A-Raf, or simply A-Raf, is ...

'' component of the PAM complex and with ''DNAJC15''. An isoform of Tim50 interacts with ''COIL'' and

snRNP snRNPs (pronounced "snurps"), or small nuclear ribonucleoproteins, are RNA-protein complexes that combine with unmodified pre-mRNA and various other proteins to form a spliceosome, a large RNA-protein molecular complex upon which splicing of pre- ...

Structure

Function

Clinical significance

Interactions

References

Further reading