Mitochondrial import inner membrane translocase subunit Tim8 A, also known as deafness-dystonia peptide or protein is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

that in humans is encoded by the ''TIMM8A''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. This

translocase Translocase is a general term for a protein that assists in moving another molecule, usually across a cell membrane. These enzymes catalyze the movement of ions or molecules across membranes or their separation within membranes. The reaction is des ...

has similarity to yeast

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 ...

l proteins that are involved in the import of metabolite transporters from the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

into the mitochondrial inner membrane. The gene is mutated in deafness-dystonia syndrome (or Mohr-Tranebjaerg syndrome; MTS/DFN-1) and it is postulated that MTS/DFN-1 is a mitochondrial disease caused by a defective mitochondrial protein import system.

Structure

The ''TIMM8A'' gene is located on q arm of chromosome X in position 22.1 and spans 3,313 base pairs. The gene produces an 11 kDa protein composed of 97

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

. The structure shows resemblance to yeast

translocase of the inner membrane The translocase of the inner membrane (TIM) is a complex of proteins found in the inner mitochondrial membrane of the mitochondria. Components of the TIM complex facilitate the translocation of proteins across the inner membrane and into the mitoc ...

(TIM) proteins with two conserved paired

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

residue motifs. The

residues organize

zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...

ions for stability and control other interactions with proteins.

Function

The human ''TIMM8A'' gene codes for a

involved in the import and insertion of hydrophobic membrane proteins from the cytoplasm into the mitochondrial inner membrane. It is also required for the transfer of beta-barrel precursors from the

TOM complex The translocase of the outer membrane (TOM) is a complex of proteins found in the outer mitochondrial membrane of the mitochondria. It allows movement of proteins through this barrier and into the intermembrane space of the mitochondrion. Mos ...

to the sorting and assembly machinery (SAM complex) of the outer membrane. It acts as a chaperone-like protein that protects the hydrophobic precursors from aggregation and guide them through the

mitochondrial intermembrane space A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used th ...

. The TIMM8-TIMM13 complex mediates the import of proteins such as

TIMM23 Mitochondrial import inner membrane translocase subunit Tim23 is an enzyme that in humans is encoded by the ''TIMM23'' gene. See also * Mitochondria Inner Membrane Translocase * TIMM17A * TIMM22 * TIMM44 Mitochondrial import inner membrane t ...

, SLC25A12/ARALAR1 and SLC25A13/ARALAR2, while the predominant TIMM9-TIMM10 70 kDa complex mediates the import of much more proteins. TIMM8A has been implicated as a required element in normal neurologic development.

Clinical significance

Mutation of TIMM8A is associated with Mohr-Tranebjaerg syndrome or deafness-dystonia syndrome, a mitochondrial disease postulated to be associated with a defective mitochondrial protein import system. Mohr-Tranebjaerg syndrome is a recessive, X-linked neurodegenerative syndrome characterized by early-onset deafness followed by progressive

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 ...

in adulthood, progressive

sensorineural hearing loss Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear or sensory organ (cochlea and associated structures) or the vestibulocochlear nerve (cranial nerve VIII). SNHL accounts for about 90% of rep ...

, mental retardation,

dysphagia Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a disease#Terminology, condition in its own right. It may be a sensation that suggests difficulty in the passag ...

paranoia Paranoia is an instinct or thought process that is believed to be heavily influenced by anxiety or fear, often to the point of delusion and irrationality. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy concer ...

, and

optic atrophy Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. Damage and death of these nerve cells, or neurons, leads to characteristic featu ...

. It is known to be caused by a truncation or deletion of the 11 kDa protein product of TIMM8A. Defects in this gene also cause Jensen syndrome, an X-linked disease with opticoacoustic nerve

atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...

and

muscle weakness Muscle weakness is a lack of muscle strength. Its causes are many and can be divided into conditions that have either true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, includi ...

. A 39-year-old Japanese male patient with a

nonsense mutation In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produc ...

of the CGA codon 80 of exon 2 by TGA in the TIMM8A gene was diagnosed with deafness-dystonia syndrome. Signs and symptoms included sensorineural deafness,

blepharospasm Blepharospasm is any abnormal contraction of the orbicularis oculi muscle. The condition should be distinguished from the more common, and milder, involuntary quivering of an eyelid, known as myokymia, or fasciculation. In most cases, blepharosp ...

, brisk

deep tendon reflexes The stretch reflex (myotatic reflex), or more accurately "muscle stretch reflex", is a muscle contraction in response to stretching within the muscle. The reflex functions to maintain the muscle at a constant length. The term deep tendon reflex is ...

and

personality changes Personality Changes: Originally thought to be concrete and unchanging, recent studies have found evidence that personality can change throughout a person's life. An important idea to keep in mind is that differences in personality traits among ind ...

. However, there were no visual or sensory disturbances. The mother was found to be a heterozygous carrier for the mutation. Another patient, an 11-year-old Dutch child with a de novo missense mutation (C66W; c.233C > G) in the TIMM8A gene, was diagnosed with sensorineural hearing impairment associated with Deafness-dystonia syndrome. Signs and symptoms included hyperreflexia, dyspraxia,

synkinesis Synkinesis is a neurological symptom in which a voluntary muscle movement causes the simultaneous involuntary contraction of other muscles. An example might be smiling inducing an involuntary contraction of the eye muscles, causing a person to squ ...

, and progressive

. A third patient, a 30-year-old male with Deafness-dystonia syndrome, was found to have a novel 108delG mutation in the TIMM8A gene. Signs and symptoms were generalized

scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...

, and involuntary movements of the head and neck. There are many more cases of mutations in the TIMM8A gene with varying symptoms, commonly including

mental deficiency Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signific ...

, and others.

Interactions

TIMM8A has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with

Signal transducing adaptor molecule Signal transducing adapter molecule 1 is a protein that in humans is encoded by the ''STAM'' gene. Function This gene was identified by the rapid tyrosine-phosphorylation of its product in response to cytokine stimulation. The encoded protein ...

and TIMM13. Three copies of TIMM8A and three copies of TIMM13 assemble to form a 70 kDa TIMM8- TIMM13 Complex with heterohexamer structure in the intermembrane space. The TIMM8-TIMM13 Complex associates with the TIM22 complex whose core is composed of

TIMM22 Mitochondrial import inner membrane translocase subunit Tim22 is an enzyme that in humans is encoded by the ''TIMM22'' gene. See also * Mitochondria Inner Membrane Translocase * TIMM17A * TIMM23 * TIMM44 Mitochondrial import inner membrane tran ...

to import and assemble inner membrane proteins.

References

External links