TIMM8A

Last updated
TIMM8A
Identifiers
Aliases TIMM8A , DDP, DDP1, DFN1, MTS, TIM8, translocase of inner mitochondrial membrane 8 homolog A (yeast), translocase of inner mitochondrial membrane 8A
External IDs OMIM: 300356 MGI: 1353433 HomoloGene: 37878 GeneCards: TIMM8A
Orthologs
SpeciesHumanMouse
Entrez

1678

30058

Ensembl

ENSG00000126953

ENSMUSG00000048007

UniProt

O60220

Q9WVA2

RefSeq (mRNA)

NM_032696
NM_001145951
NM_004085

NM_013898

RefSeq (protein)

NP_001139423
NP_004076

NP_038926

Location (UCSC) Chr X: 101.35 – 101.35 Mb Chr X: 133.44 – 133.44 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Mitochondrial import inner membrane translocase subunit Tim8 A, also known as deafness-dystonia peptide or protein is an enzyme that in humans is encoded by the TIMM8A gene. [5] [6] [7] This translocase has similarity to yeast mitochondrial proteins that are involved in the import of metabolite transporters from the cytoplasm 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. [7]

Contents

Structure

The TIMM8A gene is located on q arm of chromosome X in position 22.1 and spans 3,313 base pairs. [8] The gene produces an 11 kDa protein composed of 97 amino acids. [9] [10] The structure shows resemblance to yeast translocase of the inner membrane (TIM) proteins with two conserved paired cysteine residue motifs. [11] The cysteine residues organize zinc ions for stability and control other interactions with proteins. [11]

Function

The human TIMM8A gene codes for a translocase involved in the import and insertion of hydrophobic membrane proteins from the cytoplasm into the mitochondrial inner membrane. [8] It is also required for the transfer of beta-barrel precursors from the TOM complex 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. The TIMM8-TIMM13 complex mediates the import of proteins such as TIMM23, 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. [12]

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. [7] Mohr-Tranebjaerg syndrome is a recessive, X-linked neurodegenerative syndrome characterized by early-onset deafness followed by progressive dystonia in adulthood, progressive sensorineural hearing loss, mental retardation, dysphagia, paranoia, and optic atrophy. [13] [14] It is known to be caused by a truncation or deletion of the 11 kDa protein product of TIMM8A. [15] Defects in this gene also cause Jensen syndrome, an X-linked disease with opticoacoustic nerve atrophy and muscle weakness. [8]

A 39-year-old Japanese male patient with a nonsense mutation 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, dystonia, blepharospasm, brisk deep tendon reflexes and personality changes. However, there were no visual or sensory disturbances. The mother was found to be a heterozygous carrier for the mutation. [13] 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, atrophy, and progressive dystonia. [16] 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 dystonia, scoliosis, blepharospasm, and involuntary movements of the head and neck. [17] There are many more cases of mutations in the TIMM8A gene with varying symptoms, commonly including dystonia, mental deficiency, sensorineural hearing loss, optic atrophy, and others. [18] [19] [20] [21] [22]

Interactions

TIMM8A has been shown to interact with Signal transducing adaptor molecule [11] and TIMM13. [23] [24] 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. [24] [12] The TIMM8-TIMM13 Complex associates with the TIM22 complex whose core is composed of TIMM22 to import and assemble inner membrane proteins. [12]

Related Research Articles

Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell. Proteins can be targeted to the inner space of an organelle, different intracellular membranes, the plasma membrane, or to the exterior of the cell via secretion. Information contained in the protein itself directs this delivery process. Correct sorting is crucial for the cell; errors or dysfunction in sorting have been linked to multiple diseases.

<span class="mw-page-title-main">TIM/TOM complex</span>

The TIM/TOM complex is a protein complex in cellular biochemistry which translocates proteins produced from nuclear DNA through the mitochondrial membrane for use in oxidative phosphorylation. In enzymology, the complex is described as an mitochondrial protein-transporting ATPase, or more systematically ATP phosphohydrolase , as the TIM part requires ATP hydrolysis to work.

<span class="mw-page-title-main">Mitochondrial membrane transport protein</span>

Mitochondrial membrane transport proteins, also known as mitochondrial carrier proteins, are proteins which exist in the membranes of mitochondria. They serve to transport molecules and other factors, such as ions, into or out of the organelles. Mitochondria contain both an inner and outer membrane, separated by the inter-membrane space, or inner boundary membrane. The outer membrane is porous, whereas the inner membrane restricts the movement of all molecules. The two membranes also vary in membrane potential and pH. These factors play a role in the function of mitochondrial membrane transport proteins. There are 53 discovered human mitochondrial membrane transporters, with many others that are known to still need discovered.

<span class="mw-page-title-main">Dynamin-like 120 kDa protein</span> Protein-coding gene in the species Homo sapiens

Dynamin-like 120 kDa protein, mitochondrial is a protein that in humans is encoded by the OPA1 gene. This protein regulates mitochondrial fusion and cristae structure in the inner mitochondrial membrane (IMM) and contributes to ATP synthesis and apoptosis, and small, round mitochondria. Mutations in this gene have been implicated in dominant optic atrophy (DOA), leading to loss in vision, hearing, muscle contraction, and related dysfunctions.

<span class="mw-page-title-main">BCS1L</span> Protein-coding gene in the species Homo sapiens

Mitochondrial chaperone BCS1 (BCS1L), also known as BCS1 homolog, ubiquinol-cytochrome c reductase complex chaperone (h-BCS1), is a protein that in humans is encoded by the BCS1L gene. BCS1L is a chaperone protein involved in the assembly of Ubiquinol Cytochrome c Reductase, which is located in the inner mitochondrial membrane and is part of the electron transport chain. Mutations in this gene are associated with mitochondrial complex III deficiency, GRACILE syndrome, and Bjoernstad syndrome.

<span class="mw-page-title-main">TIMM13</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit Tim13 is an enzyme that in humans is encoded by the TIMM13 gene.

<span class="mw-page-title-main">Translocase of the outer membrane</span>

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. Most of the proteins needed for mitochondrial function are encoded by the nucleus of the cell. The outer membrane of the mitochondrion is impermeable to large molecules greater than 5000 daltons. The TOM works in conjunction with the translocase of the inner membrane (TIM) to translocate proteins into the mitochondrion. Many of the proteins in the TOM complex, such as TOMM22, were first identified in Neurospora crassa and Saccharomyces cerevisiae. Many of the genes encoding these proteins are designated as TOMM (translocase of the outer mitochondrial membrane) complex genes.

<span class="mw-page-title-main">TIMM10</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit Tim10 is an enzyme that in humans is encoded by the TIMM10 gene.

<span class="mw-page-title-main">TIMM44</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit TIM44 is an enzyme that in humans is encoded by the TIMM44 gene.

<span class="mw-page-title-main">TIMM10B</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit Tim9 B is an enzyme that in humans is encoded by the FXC1 gene.

<span class="mw-page-title-main">TIMM23</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit Tim23 is an enzyme that in humans is encoded by the TIMM23 gene.

<span class="mw-page-title-main">DNAJC19</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit TIM14 is an enzyme that in humans is encoded by the DNAJC19 gene on chromosome 3. TIM14 belongs to the DnaJ family, which has been involved in Hsp40/Hsp70 chaperone systems. As a mitochondrial chaperone, TIM14 functions as part of the TIM23 complex import motor to facilitate the import of nuclear-encoded proteins into the mitochondria. TIM14 also complexes with prohibitin complexes to regulate mitochondrial morphogenesis, and has been implicated in dilated cardiomyopathy with ataxia.

<span class="mw-page-title-main">TIMM9</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit Tim9 is an enzyme that in humans is encoded by the TIMM9 gene.

<span class="mw-page-title-main">TIMM22</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit Tim22 is an enzyme that in humans is encoded by the TIMM22 gene.

<span class="mw-page-title-main">TIMM50</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit TIM50 is a protein that in humans is encoded by the TIMM50 gene. Tim50 is a subunit of the Tim23 translocase complex in the inner mitochondrial membrane. Mutations in TIMM50 can lead to epilepsy, severe intellectual disability, and 3-methylglutaconic aciduria. TIMM50 expression is increased in breast cancer cells and decreased in hypertrophic hearts.

<span class="mw-page-title-main">Björnstad syndrome</span> Medical condition

Björnstad syndrome is an autosomal recessive congenital condition involving pili torti, sensorineural deafness, and hair abnormalities. It was first characterized in 1965, in Oslo, by prof. Roar Theodor Bjørnstad after he observed an association between pili torti and hearing loss. The condition is extremely rare, with less than 50 cases documented in medical literature worldwide.

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 mitochondrial matrix. They also facilitate the insertion of proteins into the inner mitochondrial membrane, where they must reside in order to function, these mainly include members of the mitochondrial carrier family of proteins.

<span class="mw-page-title-main">Mohr–Tranebjærg syndrome</span> Medical condition

Mohr–Tranebjærg syndrome (MTS) is a rare X-linked recessive syndrome also known as deafness–dystonia syndrome and caused by mutation in the TIMM8A gene. It is characterized by clinical manifestations commencing with early childhood onset hearing loss, followed by adolescent onset progressive dystonia or ataxia, visual impairment from early adulthood onwards and dementia from the 4th decade onwards. The severity of the symptoms may vary, but they progress usually to severe deafness and dystonia and sometimes are accompanied by cortical deterioration of vision and mental deterioration.

<span class="mw-page-title-main">SERAC1</span> Protein-coding gene in the species Homo sapiens

Serine active site-containing protein 1, or Protein SERAC1 is a protein in humans that is encoded by the SERAC1 gene. The protein encoded by this gene is a phosphatidylglycerol remodeling protein found at the interface of mitochondria and endoplasmic reticula, where it mediates phospholipid exchange. The encoded protein plays a major role in mitochondrial function and intracellular cholesterol trafficking. Defects in this gene are a cause of 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL). Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene.

Mitochondrial processing peptidase is an enzyme complex found in mitochondria which cleaves signal sequences from mitochondrial proteins. In humans this complex is composed of two subunits encoded by the genes PMPCA, and PMPCB. The enzyme is also known as. This enzyme catalyses the following chemical reaction

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000126953 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000048007 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Jin H, Kendall E, Freeman TC, Roberts RG, Vetrie DL (November 1999). "The human family of Deafness/Dystonia peptide (DDP) related mitochondrial import proteins". Genomics. 61 (3): 259–67. doi:10.1006/geno.1999.5966. PMID   10552927.
  6. ↑ Jin H, May M, Tranebjaerg L, Kendall E, Fontán G, Jackson J, et al. (October 1996). "A novel X-linked gene, DDP, shows mutations in families with deafness (DFN-1), dystonia, mental deficiency and optic atrophy". Nature Genetics. 14 (2): 177–80. doi:10.1038/ng1096-177. PMID   8841189. S2CID   22065091.
  7. 1 2 3 "Entrez Gene: TIMM8A translocase of inner mitochondrial membrane 8 homolog A (yeast)".
  8. 1 2 3 "Entrez Gene: TIMM8A translocase of inner mitochondrial membrane 8A".
  9. ↑ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, et al. (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC   4076475 . PMID   23965338.
  10. ↑ "TIMM8A - Mitochondrial import inner membrane translocase subunit Tim8 A". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  11. 1 2 3 Blackstone C, Roberts RG, Seeburg DP, Sheng M (May 2003). "Interaction of the deafness-dystonia protein DDP/TIMM8a with the signal transduction adaptor molecule STAM1". Biochemical and Biophysical Research Communications. 305 (2): 345–52. doi:10.1016/S0006-291X(03)00767-8. PMID   12745081.
  12. 1 2 3 "TIMM8A - translocase of inner mitochondrial membrane 8A, mitochondrial". UniProt.org. The UniProt Consortium.
  13. 1 2 Ujike H, Tanabe Y, Takehisa Y, Hayabara T, Kuroda S (June 2001). "A family with X-linked dystonia-deafness syndrome with a novel mutation of the DDP gene". Archives of Neurology. 58 (6): 1004–7. doi:10.1001/archneur.58.6.1004. PMID   11405816.
  14. ↑ Bauer MF, Rothbauer U, Mühlenbein N, Smith RJ, Gerbitz K, Neupert W, et al. (December 1999). "The mitochondrial TIM22 preprotein translocase is highly conserved throughout the eukaryotic kingdom". FEBS Letters. 464 (1–2): 41–7. doi: 10.1016/S0014-5793(99)01665-8 . PMID   10611480.
  15. ↑ Koehler CM, Leuenberger D, Merchant S, Renold A, Junne T, Schatz G (March 1999). "Human deafness dystonia syndrome is a mitochondrial disease". Proceedings of the National Academy of Sciences of the United States of America. 96 (5): 2141–6. Bibcode:1999PNAS...96.2141K. doi: 10.1073/pnas.96.5.2141 . PMC   26750 . PMID   10051608.
  16. ↑ Tranebjaerg L, Hamel BC, Gabreels FJ, Renier WO, Van Ghelue M (June 2000). "A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness-dystonia-optic atrophy syndrome". European Journal of Human Genetics. 8 (6): 464–7. doi: 10.1038/sj.ejhg.5200483 . PMID   10878669.
  17. ↑ Swerdlow RH, Wooten GF (October 2001). "A novel deafness/dystonia peptide gene mutation that causes dystonia in female carriers of Mohr-Tranebjaerg syndrome". Annals of Neurology. 50 (4): 537–40. doi:10.1002/ana.1160. PMID   11601506. S2CID   28334892.
  18. ↑ Dulski J, Schinwelski M, Mandat T, Pienczk-Ręcławowicz K, Sławek J (2016). "Long-Term Follow-Up with Video of a Patient with Deafness-Dystonia Syndrome Treated with DBS-GPi". Stereotactic and Functional Neurosurgery. 94 (2): 123–5. doi:10.1159/000445078. PMID   27100856. S2CID   46846035.
  19. ↑ Shaker M, Lorigiano TH, Vadlamudi A (June 2016). "Xq22.1 contiguous gene deletion syndrome of X-linked agammaglobulinemia and Mohr-Tranebjærg syndrome". Annals of Allergy, Asthma & Immunology. 116 (6): 578–9. doi:10.1016/j.anai.2016.03.014. PMID   27048950.
  20. ↑ Aguirre LA, Pérez-Bas M, Villamar M, López-Ariztegui MA, Moreno-Pelayo MA, Moreno F, del Castillo I (December 2008). "A Spanish sporadic case of deafness-dystonia (Mohr-Tranebjaerg) syndrome with a novel mutation in the gene encoding TIMM8a, a component of the mitochondrial protein translocase complexes". Neuromuscular Disorders. 18 (12): 979–81. doi:10.1016/j.nmd.2008.09.009. PMID   18952432. S2CID   27598478.
  21. ↑ Aguirre LA, del Castillo I, Macaya A, Medá C, Villamar M, Moreno-Pelayo MA, Moreno F (February 2006). "A novel mutation in the gene encoding TIMM8a, a component of the mitochondrial protein translocase complexes, in a Spanish familial case of deafness-dystonia (Mohr-Tranebjaerg) syndrome". American Journal of Medical Genetics. Part A. 140 (4): 392–7. doi:10.1002/ajmg.a.31079. PMID   16411215. S2CID   27887064.
  22. ↑ Kreisel SH, Binder J, Wöhrle JC, Krauss JK, Hofmann S, Bauer MF, et al. (October 2004). "Dystonia in the Mohr-Tranebjaerg syndrome responds to GABAergic substances". Movement Disorders. 19 (10): 1241–3. doi:10.1002/mds.20150. PMID   15390009. S2CID   31590188.
  23. ↑ Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC   1847948 . PMID   17353931.
  24. 1 2 Roesch K, Curran SP, Tranebjaerg L, Koehler CM (March 2002). "Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex". Human Molecular Genetics. 11 (5): 477–86. doi: 10.1093/hmg/11.5.477 . PMID   11875042.

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