Abstract
Loss of mitochondrial function not only causes specific mitochondrial diseases but also contributes to serious conditions such as neurodegeneration and diabetes. Since mitochondrial DNA is transcribed as a polycistronic message comprised of three forms of RNA (rRNA, mRNA, and tRNA), proper 5′- and 3′-end cleavage is essential. In the nucleus, tRNA 5′-end processing is carried out by the first identified ribozyme, RNase P. In contrast, mitochondrial tRNAs are processed by a three-protein complex, mitochondrial RNase P, which does not have an RNA component. An accessory subcomplex made of the m1A9 methyltransferase MRPP1 and the dehydrogenase MRPP2 binds to the metallonuclease MRPP3 that cleaves the RNA phosphodiester backbone. Each protein has been shown to be essential in model organisms, and loss of each gives rise to human multisystemic diseases with many characteristics of mitochondrial disease. In this review, we discuss what is known about the mitochondrial RNase P complex, the molecular mechanism of 5′-end mitochondrial tRNA processing, and how loss of this activity causes human disease.
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References
Akagawa S et al (2017) Japanese male siblings with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (HSD10 disease) without neurological regression. JIMD Rep 32:81–85. https://doi.org/10.1007/8904_2016_570
Akawi NA et al (2016) A homozygous splicing mutation in ELAC2 suggests phenotypic variability including intellectual disability with minimal cardiac involvement. Orphanet J Rare Dis 11:139. https://doi.org/10.1186/s13023-016-0526-8
Anderson S et al (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457–465
Antonicka H, Shoubridge EA (2015) Mitochondrial RNA granules are centers for posttranscriptional RNA processing and ribosome biogenesis. Cell Rep. https://doi.org/10.1016/j.celrep.2015.01.030
Antonicka H, Sasarman F, Nishimura T, Paupe V, Shoubridge EA (2013) The mitochondrial RNA-binding protein GRSF1 localizes to RNA granules and is required for posttranscriptional mitochondrial gene expression. Cell Metab 17:386–398. https://doi.org/10.1016/j.cmet.2013.02.006
Bellen HJ et al (2004) The BDGP gene disruption project: single transposon insertions associated with 40% of Drosophila genes. Genetics 167:761–781. https://doi.org/10.1534/genetics.104.026427
Borowski LS, Dziembowski A, Hejnowicz MS, Stepien PP, Szczesny RJ (2013) Human mitochondrial RNA decay mediated by PNPase–hSuv3 complex takes place in distinct foci. Nucleic Acids Res 41:1223–1240. https://doi.org/10.1093/nar/gks1130
Brandon MC, Lott MT, Nguyen KC, Spolim S, Navathe SB, Baldi P, Wallace DC (2005) MITOMAP: a human mitochondrial genome database—2004 update. Nucleic Acids Res 33:D611–D613. https://doi.org/10.1093/nar/gki079
Brzezniak LK, Bijata M, Szczesny RJ, Stepien PP (2011) Involvement of human ELAC2 gene product in 3′ end processing of mitochondrial tRNAs. RNA Biol 8:616–626. https://doi.org/10.4161/rna.8.4.15393
Chatfield KC et al (2015) Mitochondrial energy failure in HSD10 disease is due to defective mtDNA transcript processing. Mitochondrion 21:1–10. https://doi.org/10.1016/j.mito.2014.12.005
Chinnery PF (2000) Mitochondrial disorders overview. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews® [Internet]. University of Washington, Seattle, pp 1993–2017
Claros MG, Vincens P (1996) Computational method to predict mitochondrially imported proteins and their targeting sequences. Eur J Biochem 241:779–786
Deutschmann AJ et al (2014) Mutation or knock-down of 17beta-hydroxysteroid dehydrogenase type 10 cause loss of MRPP1 and impaired processing of mitochondrial heavy strand transcripts. Hum Mol Genet 23:3618–3628. https://doi.org/10.1093/hmg/ddu072
Dubrovsky EB, Dubrovskaya VA, Levinger L, Schiffer S, Marchfelder A (2004) Drosophila RNase Z processes mitochondrial and nuclear pre-tRNA 3′ ends in vivo. Nucleic Acids Res 32:255–262. https://doi.org/10.1093/nar/gkh182
Falk MJ et al (2016) A novel HSD17B10 mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression. RNA Biol 13:477–485. https://doi.org/10.1080/15476286.2016.1159381
Fukao T et al (2014) The first case in Asia of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (HSD10 disease) with atypical presentation. J Hum Genet 59:609–614. https://doi.org/10.1038/jhg.2014.79
Gobert A et al (2010) A single Arabidopsis organellar protein has RNase P activity. Nat Struct Mol Biol 17:740. doi:https://doi.org/10.1038/nsmb.1812. https://www.nature.com/articles/nsmb.1812—supplementary-information
Gray MW (2012) Mitochondrial evolution. Cold Spring Harb Perspect Biol 4:a011403. https://doi.org/10.1101/cshperspect.a011403
Guan MX, Enriquez JA, Fischel-Ghodsian N, Puranam RS, Lin CP, Maw MA, Attardi G (1998) The deafness-associated mitochondrial DNA mutation at position 7445, which affects tRNASer(UCN) precursor processing, has long-range effects on NADH dehydrogenase subunit ND6 gene expression. Mol Cell Biol 18:5868–5879
Guo L, Yuan Y, Bi R (2016) Mitochondrial DNA mutation m.5512A > G in the acceptor-stem of mitochondrial tRNATrp causing maternally inherited essential hypertension. Biochem Biophys Res Commun 479:800–807. https://doi.org/10.1016/j.bbrc.2016.09.129
Haack TB et al (2013) ELAC2 mutations cause a mitochondrial RNA processing defect associated with hypertrophic cardiomyopathy. Am J Hum Genet 93:211–223. https://doi.org/10.1016/j.ajhg.2013.06.006
Hochberg I et al (2017) A homozygous variant in mitochondrial RNase P subunit PRORP is associated with Perrault syndrome characterized by hearing loss and primary ovarian insufficiency. BioRxiv. https://doi.org/10.1101/168252
Holzmann J, Frank P, Löffler E, Bennett KL, Gerner C, Rossmanith W (2008) RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme. Cell 135:462–474. https://doi.org/10.1016/j.cell.2008.09.013
Howard MJ, Lim WH, Fierke CA, Koutmos M (2012) Mitochondrial ribonuclease P structure provides insight into the evolution of catalytic strategies for precursor-tRNA 5′ processing. Proc Natl Acad Sci U S A 109:16149–16154. https://doi.org/10.1073/pnas.1209062109
Iborra FJ, Kimura H, Cook PR (2004) The functional organization of mitochondrial genomes in human cells. BMC Biol 2:9. https://doi.org/10.1186/1741-7007-2-9
Jablonski JA, Caputi M (2009) Role of cellular RNA processing factors in human immunodeficiency virus type 1 mRNA metabolism, replication, and infectivity. J Virol 83:981–992. https://doi.org/10.1128/JVI.01801-08
Jackman JE, Montange RK, Malik HS, Phizicky EM (2003) Identification of the yeast gene encoding the tRNA m1G methyltransferase responsible for modification at position 9. RNA 9:574–585. https://doi.org/10.1261/rna.5070303
Jenkinson EM et al (2012) Perrault syndrome: further evidence for genetic heterogeneity. J Neurol 259:974–976. https://doi.org/10.1007/s00415-011-6285-5
Jiang P et al (2016) A hypertension-associated tRNAAla mutation alters tRNA metabolism and mitochondrial function. Mol Cell Biol 36:1920–1930. https://doi.org/10.1128/MCB.00199-16
Jourdain AA, Koppen M, Wydro M, Rodley CD, Lightowlers RN, Chrzanowska-Lightowlers ZM, Martinou JC (2013) GRSF1 regulates RNA processing in mitochondrial RNA granules. Cell Metab 17:399–410. https://doi.org/10.1016/j.cmet.2013.02.005
Kash JC, Cunningham DM, Smit MW, Park Y, Fritz D, Wilusz J, Katze MG (2002) Selective translation of eukaryotic mRNAs: functional molecular analysis of GRSF-1, a positive regulator of influenza virus protein synthesis. J Virol 76:10417–10426. https://doi.org/10.1128/JVI.76.20.10417-10426.2002
Kissinger CR et al (2004) Crystal structure of human ABAD/HSD10 with a bound inhibitor: implications for design of Alzheimer’s disease therapeutics. J Mol Biol 342:943–952. https://doi.org/10.1016/j.jmb.2004.07.071
Klemm BP, Wu N, Chen Y, Liu X, Kaitany KJ, Howard MJ, Fierke CA (2016) The diversity of ribonuclease P: protein and RNA catalysts with analogous biological functions. Biomol Ther 6. https://doi.org/10.3390/biom6020027
Korman SH (2006) Inborn errors of isoleucine degradation: a review. Mol Genet Metab 89:289–299. https://doi.org/10.1016/j.ymgme.2006.07.010
Land M et al (2015) Insights from 20 years of bacterial genome sequencing. Funct Integr Genomics 15:141–161. https://doi.org/10.1007/s10142-015-0433-4
Levinger L, Jacobs O, James M (2001) In vitro 3′-end endonucleolytic processing defect in a human mitochondrial tRNASer(UCN) precursor with the U7445C substitution, which causes non-syndromic deafness. Nucleic Acids Res 29:4334–4340
Levinger L, Giege R, Florentz C (2003) Pathology-related substitutions in human mitochondrial tRNAIle reduce precursor 3′ end processing efficiency in vitro. Nucleic Acids Res 31:1904–1912
Levinger L, Oestreich I, Florentz C, Mörl M (2004) A pathogenesis-associated mutation in human mitochondrial tRNALeu(UUR) leads to reduced 3′-end processing and CCA addition. J Mol Biol 337:535–544. https://doi.org/10.1016/j.jmb.2004.02.008
Lewis OL, Farr CL, Kaguni LS (1995) Drosophila melanogaster Mitochondrial DNA: completion of the nucleotide sequence and evolutionary comparisons. Insect Mol Biol 4:263–278. https://doi.org/10.1111/j.1365-2583.1995.tb00032.x
Li R, Liu Y, Li Z, Yang L, Wang S, Guan MX (2009) Failures in mitochondrial tRNAMet and tRNAGln metabolism caused by the novel 4401A>G mutation are involved in essential hypertension in a Han Chinese family. Hypertension 54:329–337. https://doi.org/10.1161/HYPERTENSIONAHA.109.129270
Liu Y, Li Y, Zhu C, Tian L, Guan M, Chen Y (2017) Mitochondrial biogenesis dysfunction and metabolic dysfunction from a novel mitochondrial tRNAMet 4467 C>A mutation in a Han Chinese family with maternally inherited hypertension. Sci Rep 7:3034. https://doi.org/10.1038/s41598-017-03303-w
Margulis L (1970) Origin of eukaryotic cells. Yale University Press, New Haven
Mercer TR et al (2011) The human mitochondrial transcriptome. Cell 146:645–658. https://doi.org/10.1016/j.cell.2011.06.051
Metodiev MD et al (2016) Recessive mutations in TRMT10C cause defects in mitochondrial RNA processing and multiple respiratory chain deficiencies. Am J Hum Genet 98:993–1000. https://doi.org/10.1016/j.ajhg.2016.03.010
Moeller G, Adamski J (2009) Integrated view on 17beta-hydroxysteroid dehydrogenases. Mol Cell Endocrinol 301:7–19. https://doi.org/10.1016/j.mce.2008.10.040
Oerum S et al (2017) Novel patient missense mutations in the HSD17B10 gene affect dehydrogenase and mitochondrial tRNA modification functions of the encoded protein. Biochim Biophys Acta 1863(12):3294–3302. https://doi.org/10.1016/j.bbadis.2017.09.002
Ofman R et al (2003) 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene. Am J Hum Genet 72:1300–1307
Ojala D, Montoya J, Attardi G (1981) tRNA punctuation model of RNA processing in human mitochondria. Nature 290:470–474
Page IH (1967) The mosaic theory of arterial hypertension—its interpretation. Perspect Biol Med 10:325–333
Park H, Davidson E, King MP (2003) The pathogenic A3243G mutation in human mitochondrial tRNALeu(UUR) decreases the efficiency of aminoacylation. Biochemistry 42:958–964. https://doi.org/10.1021/bi026882r
Perez-Cerda C et al (2005) 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: an X-linked inborn error of isoleucine metabolism that may mimic a mitochondrial disease. Pediatr Res 58:488–491. https://doi.org/10.1203/01.pdr.0000176916.94328.cd
Powell CA, Nicholls TJ, Minczuk M (2015) Nuclear-encoded factors involved in post-transcriptional processing and modification of mitochondrial tRNAs in human disease. Front Genet 6:79. https://doi.org/10.3389/fgene.2015.00079
Rackham O et al (2016) Hierarchical RNA processing is required for mitochondrial ribosome assembly. Cell Rep 16:1874–1890. https://doi.org/10.1016/j.celrep.2016.07.031
Rauschenberger K et al (2010) A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. EMBO Mol Med 2:51–62. https://doi.org/10.1002/emmm.200900055
Reid FM, Rovio A, Holt IJ, Jacobs HT (1997) Molecular phenotype of a human lymphoblastoid cell-line homoplasmic for the np 7445 deafness-associated mitochondrial mutation. Hum Mol Genet 6:443–449
Reinhard L, Sridhara S, Hällberg BM (2017) The MRPP1/MRPP2 complex is a tRNA-maturation platform in human mitochondria. Nucleic Acids Res 45(21):12469–12480. https://doi.org/10.1093/nar/gkx902
Richardson A, Berry GT, Garganta C, Abbott MA (2016) Hydroxysteroid 17-beta dehydrogenase type 10 disease in siblings. JIMD Rep 32:25–32. https://doi.org/10.1007/8904_2016_547
Robertson HD, Altman S, Smith JD (1972) Purification and properties of a specific Escherichia coli ribonuclease which cleaves a tyrosine transfer ribonucleic acid precursor. J Biol Chem 247:5243–5251
Sanchez MI et al (2011) RNA processing in human mitochondria. Cell Cycle 10:2904–2916. https://doi.org/10.4161/cc.10.17.17060
Schaub MC, Lopez SR, Caputi M (2007) Members of the heterogeneous nuclear ribonucleoprotein H family activate splicing of an HIV-1 splicing substrate by promoting formation of ATP-dependent spliceosomal complexes. J Biol Chem 282:13617–13626
Seaver LH et al (2011) A novel mutation in the HSD17B10 gene of a 10-year-old boy with refractory epilepsy, choreoathetosis and learning disability. PLoS One 6:e27348. https://doi.org/10.1371/journal.pone.0027348
Sen A, Cox RT (2017) Fly models of human diseases: Drosophila as a model for understanding human mitochondrial mutations and disease. Curr Top Dev Biol 121:1–27. https://doi.org/10.1016/bs.ctdb.2016.07.001
Sen A, Karasik A, Shanmuganathan A, Mirkovic E, Koutmos M, Cox RT (2016) Loss of the mitochondrial protein-only ribonuclease P complex causes aberrant tRNA processing and lethality in Drosophila. Nucleic Acids Res 44:6409–6422. https://doi.org/10.1093/nar/gkw338
Shafqat N et al (2003) Expanded substrate screenings of human and Drosophila type 10 17β-hydroxysteroid dehydrogenases (HSDs) reveal multiple specificities in bile acid and steroid hormone metabolism: characterization of multifunctional 3α/7α/7β/17β/20β/21-HSD. Biochem J 376:49–60
Shao Z et al (2014) Crystal structure of tRNA m1G9 methyltransferase Trm10: insight into the catalytic mechanism and recognition of tRNA substrate. Nucleic Acids Res 42:509–525. https://doi.org/10.1093/nar/gkt869
Spradling AC et al (1999) The Berkeley Drosophila genome project gene disruption project: single P-element insertions mutating 25% of vital Drosophila genes. Genetics 153:135–177
Sutton VR, O'Brien WE, Clark GD, Kim J, Wanders RJ (2003) 3-Hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 26:69–71
Taanman J-W (1999) The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta 1410:103–123. https://doi.org/10.1016/S0005-2728(98)00161-3
Taschner A, Weber C, Buzet A, Hartmann Roland K, Hartig A, Rossmanith W (2012) Nuclear RNase P of Trypanosoma brucei: a single protein in place of the multicomponent RNA-protein complex. Cell Rep 2:19–25. https://doi.org/10.1016/j.celrep.2012.05.021
Torroja L, Ortuno-Sahagun D, Ferrus A, Hammerle B, Barbas JA (1998) scully, an essential gene of Drosophila, is homologous to mammalian mitochondrial type II L-3-hydroxyacyl-CoA dehydrogenase/amyloid-beta peptide-binding protein. J Cell Biol 141:1009–1017
Van Haute L, Pearce SF, Powell CA, D'Souza AR, Nicholls TJ, Minczuk M (2015) Mitochondrial transcript maturation and its disorders. J Inherit Metab Dis 38:655–680. https://doi.org/10.1007/s10545-015-9859-z
Vilardo E, Rossmanith W (2015) Molecular insights into HSD10 disease: impact of SDR5C1 mutations on the human mitochondrial RNase P complex. Nucleic Acids Res 43:5112–5119. https://doi.org/10.1093/nar/gkv408
Vilardo E, Nachbagauer C, Buzet A, Taschner A, Holzmann J, Rossmanith W (2012) A subcomplex of human mitochondrial RNase P is a bifunctional methyltransferase—extensive moonlighting in mitochondrial tRNA biogenesis. Nucleic Acids Res 40:11583–11593. https://doi.org/10.1093/nar/gks910
Wang S et al (2011) Maternally inherited essential hypertension is associated with the novel 4263A>G mutation in the mitochondrial tRNAIle gene in a large Han Chinese family. Circ Res 108:862–870. https://doi.org/10.1161/CIRCRESAHA.110.231811
Xie X, Dubrovskaya VA, Dubrovsky EB (2011) RNAi knockdown of dRNaseZ, the Drosophila homolog of ELAC2, impairs growth of mitotic and endoreplicating tissues. Insect Biochem Mol Biol 41:167–177. https://doi.org/10.1016/j.ibmb.2010.12.001
Xie X, Dubrovskaya V, Yacoub N, Walska J, Gleason T, Reid K, Dubrovsky EB (2013) Developmental roles of Drosophila tRNA processing endonuclease RNase ZL as revealed with a conditional rescue system. Dev Biol 381:324–340. https://doi.org/10.1016/j.ydbio.2013.07.005
Xu F et al (2008) Disruption of a mitochondrial RNA-binding protein gene results in decreased cytochrome b expression and a marked reduction in ubiquinol–cytochrome c reductase activity in mouse heart mitochondria. Biochem J 416:15
Yang SY et al (2009) Mental retardation linked to mutations in the HSD17B10 gene interfering with neurosteroid and isoleucine metabolism. Proc Natl Acad Sci U S A 106:14820–14824. https://doi.org/10.1073/pnas.0902377106
Yang S-Y, He X-Y, Isaacs C, Dobkin C, Miller D, Philipp M (2014) Roles of 17β-hydroxysteroid dehydrogenase type 10 in neurodegenerative disorders. J Steroid Biochem Mol Biol 143:460–472. https://doi.org/10.1016/j.jsbmb.2014.07.001
Yogev O, Pines O (2011) Dual targeting of mitochondrial proteins: mechanism, regulation and function. Biochim Biophys Acta 1808:1012–1020. https://doi.org/10.1016/j.bbamem.2010.07.004
Zhang Y (2008) I-TASSER server for protein 3D structure prediction. BMC Bioinformatics 9:40. https://doi.org/10.1186/1471-2105-9-40
Zhu HY, Wang SW, Liu L, Li YH, Chen R, Wang L, Holliman CJ (2009) A mitochondrial mutation A4401G is involved in the pathogenesis of left ventricular hypertrophy in Chinese hypertensives. Eur J Hum Genet 17:172–178. https://doi.org/10.1038/ejhg.2008.151
Zschocke J (2012) HSD10 disease: clinical consequences of mutations in the HSD17B10 gene. J Inherit Metab Dis 35:81–89. https://doi.org/10.1007/s10545-011-9415-4
Zschocke J, Ruiter JP, Brand J, Lindner M, Hoffmann GF, Wanders RJ, Mayatepek E (2000) Progressive infantile neurodegeneration caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency: a novel inborn error of branched-chain fatty acid and isoleucine metabolism. Pediatr Res 48:852–855. https://doi.org/10.1203/00006450-200012000-00025
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This work was supported by the National Institutes of Health/Department of Defense [CHIRP HU0001–14–2-0041 to M.S. and R.T.C.].
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Saoji, M., Cox, R.T. (2018). Mitochondrial RNase P Complex in Animals: Mitochondrial tRNA Processing and Links to Disease. In: Cruz-Reyes, J., Gray, M. (eds) RNA Metabolism in Mitochondria. Nucleic Acids and Molecular Biology, vol 34. Springer, Cham. https://doi.org/10.1007/978-3-319-78190-7_3
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