Mitochondrial import inner membrane translocase subunit TIM14 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 ''DNAJC19''

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 ...

on chromosome 3. TIM14 belongs to the DnaJ family, which has been involved in Hsp40/Hsp70 chaperone systems. As a

mitochondrial 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 use ...

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 Prohibitin, also known as PHB, is a protein that in humans is encoded by the ''PHB'' gene. The ''Phb'' gene has also been described in animals, fungi, plants, and unicellular eukaryotes. Prohibitins are divided in two classes, termed Type-I and Ty ...

complexes to regulate mitochondrial morphogenesis, and has been implicated in dilated cardiomyopathy with ataxia.

Structure

The ''DNAJC19'' gene is located on the

q arm In genetics, a locus (plural loci) is a specific, fixed position on a chromosome where a particular gene or genetic marker is located. Each chromosome carries many genes, with each gene occupying a different position or locus; in humans, the total ...

of chromosome 3 at position 26.33 and it spans 6,065 base pairs. The ''DNAJC19'' gene produces a 6.29 kDa protein composed of 59

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 protein encoded by the ''DNAJC19'' gene possesses an unusual structure compared to the rest of the DNAJ protein family. Notably, the DNAJ domain of TIM14 is located at the C-terminal rather than the

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 ...

, and the

transmembrane A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

domain confers membrane-bound localization for TIM14 while other DNAJ proteins are cytosolic. TIM14 orthologs in other species, such as the yeast Tim14 and Mdj2p proteins, confirm localization to the mitochondrial inner membrane.

Function

TIM14 is required for the ATP-dependent import of mitochondrial pre-proteins into the mitochondrial matrix. The J-domain of TIM14 stimulates mtHsp70

ATPase ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...

activity to power this transport. Additionally, TIM14 helps regulate mitochondrial morphology by complexing with prohibitins to perform disphosphoglycerolipid

cardiolipin Cardiolipin (IUPAC name 1,3-bis(''sn''-3’-phosphatidyl)-''sn''-glycerol) is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition. It can also be found in the membranes of most ...

(CL) remodeling. CL is a key

phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

in mitochondrial membranes that modulates the fusion and fission of mitochondrial membranes, as well as mitophagy and

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

Clinical significance

Defects in DNAJC19 have been observed primarily in cases of dilated cardiomyopathy with ataxia (DCMA), though it has also been associated with

growth failure Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...

, microcytic anemia, and male genital anomalies. DNAJC19 was first implicated in DCMA in a study on the consanguineous Hutterite population, which has since been confirmed in other European populations. In the clinic, DNAJC19 mutations can be detected by screening for elevated levels of

3-methylglutaconic acid 3-Methylglutaconic acid is a glutarate which builds up in the urine in 3-methylglutaconic aciduria or 3-hydroxy-3-methylglutaric aciduria. See also * Glutaconic acid ''trans''-Glutaconic acid is an organic compound with formula HO2CCH=CHCH2CO2 ...

, mitochondrial distress, dilated cardiomyopathy, prolongation of the

QT interval The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave, and approximates to the time taken ...

in the electrocardiogram, and

cerebellar ataxia Cerebellar ataxia is a form of ataxia originating in the cerebellum. Non-progressive congenital ataxia (NPCA) is a classical presentation of cerebral ataxias. Cerebellar ataxia can occur as a result of many diseases and may present with symptoms ...

Interactions

TIM14 interacts with: *

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 Protein-protein interaction, interact with ARAF. See also * Translocase of the in ...

, * mtHsp70, * TIMM16/

PAM16 Mitochondrial import inner membrane translocase subunit TIM16 also known as presequence translocated-associated motor subunit PAM16, mitochondria-associated granulocyte macrophage CSF-signaling molecule, or presequence translocated-associated moto ...

, and * PHB2.

Structure

Function

Clinical significance

Interactions

References

Further reading