DNAJC19 explained

Mitochondrial import inner membrane translocase subunit TIM14 is an enzyme that in humans is encoded by the DNAJC19 gene on chromosome 3.^{[1] [2]} TIM14 belongs to the DnaJ family, which has been involved in Hsp40/Hsp70 chaperone systems.^{[3] [4]} 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.^[3] TIM14 also complexes with prohibitin complexes to regulate mitochondrial morphogenesis, and has been implicated in dilated cardiomyopathy with ataxia.^[5]

Structure

The DNAJC19 gene is located on the q arm 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.^{[6] [7]} 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, and the transmembrane 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.^[8]

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 activity to power this transport.^[3]

Additionally, TIM14 helps regulate mitochondrial morphology by complexing with prohibitins to perform disphosphoglycerolipid cardiolipin (CL) remodeling. CL is a key phospholipid in mitochondrial membranes that modulates the fusion and fission of mitochondrial membranes, as well as mitophagy and apoptosis.^[5]

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, 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.^{[4] [9]} In the clinic, DNAJC19 mutations can be detected by screening for elevated levels of 3-methylglutaconic acid, mitochondrial distress, dilated cardiomyopathy, prolongation of the QT interval in the electrocardiogram, and cerebellar ataxia.^{[9] [10]}

Interactions

TIM14 interacts with:

• TIMM44,^[3]
• mtHsp70,^[3]
• TIMM16/PAM16,^[11] and
• PHB2.^[5]

Further reading

• Sparkes R, Patton D, Bernier F . Cardiac features of a novel autosomal recessive dilated cardiomyopathic syndrome due to defective importation of mitochondrial protein . Cardiology in the Young . 17 . 2 . 215–7 . April 2007 . 17244376 . 10.1017/S1047951107000042 . 30970157 .
• Davey KM, Parboosingh JS, McLeod DR, Chan A, Casey R, Ferreira P, Snyder FF, Bridge PJ, Bernier FP . Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition . Journal of Medical Genetics . 43 . 5 . 385–93 . May 2006 . 16055927 . 2564511 . 10.1136/jmg.2005.036657 .
• Mokranjac D, Sichting M, Neupert W, Hell K . Tim14, a novel key component of the import motor of the TIM23 protein translocase of mitochondria . The EMBO Journal . 22 . 19 . 4945–56 . October 2003 . 14517234 . 204468 . 10.1093/emboj/cdg485 .
• Taylor SW, Fahy E, Zhang B, Glenn GM, Warnock DE, Wiley S, Murphy AN, Gaucher SP, Capaldi RA, Gibson BW, Ghosh SS . Characterization of the human heart mitochondrial proteome . Nature Biotechnology . 21 . 3 . 281–6 . March 2003 . 12592411 . 10.1038/nbt793 . 27329521 .
• Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ . Shotgun sequencing of the human transcriptome with ORF expressed sequence tags . Proceedings of the National Academy of Sciences of the United States of America . 97 . 7 . 3491–6 . March 2000 . 10737800 . 16267 . 10.1073/pnas.97.7.3491 . 2000PNAS...97.3491D . free .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .

Notes and References

1. Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA . 6 . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proceedings of the National Academy of Sciences of the United States of America . 99 . 26 . 16899–903 . December 2002 . 12477932 . 139241 . 10.1073/pnas.242603899 . 2002PNAS...9916899M . free .
2. Web site: Entrez Gene: DNAJC19 DnaJ (Hsp40) homolog, subfamily C, member 19.
3. Mokranjac D, Sichting M, Neupert W, Hell K . Tim14, a novel key component of the import motor of the TIM23 protein translocase of mitochondria . The EMBO Journal . 22 . 19 . 4945–56 . October 2003 . 14517234 . 204468 . 10.1093/emboj/cdg485 .
4. Davey KM, Parboosingh JS, McLeod DR, Chan A, Casey R, Ferreira P, Snyder FF, Bridge PJ, Bernier FP . Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition . Journal of Medical Genetics . 43 . 5 . 385–93 . May 2006 . 16055927 . 2564511 . 10.1136/jmg.2005.036657 .
5. Richter-Dennerlein R, Korwitz A, Haag M, Tatsuta T, Dargazanli S, Baker M, Decker T, Lamkemeyer T, Rugarli EI, Langer T . DNAJC19, a mitochondrial cochaperone associated with cardiomyopathy, forms a complex with prohibitins to regulate cardiolipin remodeling . Cell Metabolism . 20 . 1 . 158–71 . July 2014 . 24856930 . 10.1016/j.cmet.2014.04.016 . free .
6. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . October 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
7. Web site: Mitochondrial import inner membrane translocase subunit TIM14 . Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) . 2018-08-21 . https://web.archive.org/web/20180821223348/https://amino.heartproteome.org/web/protein/F2Z3A7 . 2018-08-21 . dead .
8. Davey KM, Parboosingh JS, McLeod DR, Chan A, Casey R, Ferreira P, Snyder FF, Bridge PJ, Bernier FP . Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition . Journal of Medical Genetics . 43 . 5 . 385–93 . May 2006 . 16055927 . 10.1136/jmg.2005.036657 . 2564511.
9. Ojala T, Polinati P, Manninen T, Hiippala A, Rajantie J, Karikoski R, Suomalainen A, Tyni T . New mutation of mitochondrial DNAJC19 causing dilated and noncompaction cardiomyopathy, anemia, ataxia, and male genital anomalies . Pediatric Research . 72 . 4 . 432–7 . October 2012 . 22797137 . 10.1038/pr.2012.92 . free .
10. Koutras C, Braun JE . J protein mutations and resulting proteostasis collapse . Frontiers in Cellular Neuroscience . 8 . 191 . Jul 2014 . 25071450 . 4086201 . 10.3389/fncel.2014.00191 . free .
11. Mokranjac D, Bourenkov G, Hell K, Neupert W, Groll M . Structure and function of Tim14 and Tim16, the J and J-like components of the mitochondrial protein import motor . The EMBO Journal . 25 . 19 . 4675–85 . October 2006 . 16977310 . 1590002 . 10.1038/sj.emboj.7601334 .