Mitochondrial DNA Transcription and Translation: Clinical Syndromes
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Essays in Biochemistry (2018) EBC20170103 https://doi.org/10.1042/EBC20170103 Review Article Mitochondrial DNA transcription and translation: clinical syndromes Veronika Boczonadi1,*, Giulia Ricci1,2,* and Rita Horvath1 1Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, U.K.; 2Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Correspondence: Rita Horvath ([email protected]) Diagnosing primary mitochondrial diseases is challenging in clinical practice. Although, de- fective oxidative phosphorylation (OXPHOS) is the common final pathway, it is unknown why different mtDNA or nuclear mutations result in largely heterogeneous and often tis- sue -specific clinical presentations. Mitochondrial tRNA (mt-tRNA) mutations are frequent causes of mitochondrial diseases both in children and adults. However numerous nu- clear mutations involved in mitochondrial protein synthesis affecting ubiquitously expressed genes have been reported in association with very tissue specific clinical manifestations suggesting that there are so far unknown factors determining the tissue specificity in mi- tochondrial translation. Most of these gene defects result in histological abnormalities and multiple respiratory chain defects in the affected organs. The clinical phenotypes are usu- ally early-onset, severe, and often fatal, implying the importance of mitochondrial transla- tion from birth. However, some rare, reversible infantile mitochondrial diseases are caused by very specific defects of mitochondrial translation. An unbiased genetic approach (whole exome sequencing, RNA sequencing) combined with proteomics and functional studies re- vealed novel factors involved in mitochondrial translation which contribute to the clinical manifestation and recovery in these rare reversible mitochondrial conditions. Introduction All eukaryotic cells contain both genomic and mtDNA and two separate protein synthesis machineries [1]. Mitochondria are essential eukaryotic organelles with the main function to produce the majority of cellular energy by oxidative phosphorylation (OXPHOS). Whilethemajority of OXPHOScompo- nents (complexes I–IV), the ATP synthase (complex V), and various factors required for mtDNA main- tenance (replication, transcription, copy number control)areencoded within the nucleus, 13polypep- tides, two ribosomal RNAs (mt-rRNAs), and 22 transfer RNAs (mt-tRNAs) are encoded within the mtDNA [1]. The expression of these molecules is fundamental for cellular functioning and is closely co-ordinated with nuclear gene expression. Mutations in some nuclear genes can cause secondary in- stability of the mitochondrial genome in the form of depletion (decreased number of mtDNA molecules in the cell), multiple deletions or accumulation of point mutations, which in turn leadstomitochon- drialdiseases inherited in a Mendelian fashion [2].Expressionofthemitochondrial genome is initi- ated by transcription of the mtDNA from bidirectional heavy andlight strand promoters to produce *These authors contributed two polycistronic transcripts [3]. Instead of initiating at individual gene-specific promoters, transcrip- equally to this work. tion of mammalian mtDNA initiates from single promoters for H- and L-strand transcription, and pro- Received: 16 February 2018 gresses around almost the entire length of the genome [4].Following endonucleolytic processing in- Revised: 17 May 2018 dividual mitochondrial mRNA (mt-mRNA), mitochondrial rNA (mt-rRNA), and mitochondrial tRNA Accepted: 21 May 2018 (mt-tRNA) transcripts undergo post-transcriptional modifications [5,6].Thetranscriptionmachineryof Version of Record published: the mtDNA is regulated by several transcription factors TFAM,TEFM and TFB2M and mitochondrial 06 July 2018 RNA polymerase POLRMT[7].The13mtDNA encoded components of the OXPHOSmachineryusing c 2018 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution 1 License 4.0 (CC BY). Essays in Biochemistry (2018) EBC20170103 https://doi.org/10.1042/EBC20170103 Figure 1. Summary of the genes and disease mechanisms implicated in mitochondrial translation deficiencies with asso- ciated clinical phenotypes the mitochondrial translation mechanism are synthesized within the mitochondria, with the participation of the mitoribosome [8,9].Theassembled mitoribosome translates the mt-mRNAs and synthesizes proteins that are rapidly inserted into the inner mitochondrial membrane and integrated into their relevant complexes to form the OXPHOS system [10]. Approximatelyone-third of mitochondrialdisorders have a presumed nuclear genetic defectofmitochondrial tran- scription and translation [11].Theidentification of the molecularbasisofthisgrouphasbeenparticularlychallenging and the recent availability of massivelyparallel sequencing have revealed several new disease genes, and unraveled new pathogenic mechanisms. Here, we present an overview of these tissue specific diseases (Figure 1). Defects of mitochondrial transcription There are several genes involved in the initiation (POLRMT, TFAM, TFB2B)and elongation (TEFM, MTERF1)in transcription of mtDNA, however only mutations in TFAM have been shown to cause human diseases to date (Table 1)[12]. TFAM The TFAM gene encodes a mitochondrial transcription factor essential for initiating mtDNA transcription, replica- tion, and nucleoid packaging [25]. Pathogenic mutations in TFAM are linked to an autosomal recessive disorder with infantile-onset progressive fatalliver failure. Infants were born with intrauterine growth restriction anddeveloped hepatopathy with elevated transaminases, conjugated hyperbilirubinemia, and hypoglycemia. Liver failure anddeath occurred in earlyinfancy[12].ThemtDNA copy number has been shown to be decreased in patient liver, muscle, and fibroblasts. Liver biopsy shows cirrhosis, micro- and macrovesicular steatosis and cholestasis and abnormal mito- chondrial morphology on electron microscopy. Biochemical enzymology in muscleshowed increased citrate synthase activity and borderline reduced RC enzyme activities [12].Based on these findings, it is likely, that mutations in other genes involved in mitochondrial transcription also resultinlow mtDNA copy numbers and acombineddefect of the enzymes of the respiratory chain. 2 c 2018 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY). Essays in Biochemistry (2018) EBC20170103 https://doi.org/10.1042/EBC20170103 Table 1 Defects of mitochondrial transcription, pre-RNA, mRNA processing and stabilization Mode of Gene Protein Clinical presentation Age of onset inheritance OMIM References TFAM Transcription factor A Mitochondrial DNA depletion Infancy AR 617156 Stiles et al. (2016) [12] syndrome 15 TRMT10C tRNA methyltransferase 10 Combined OXPHOS deficiency 30 Infancy AR 616974 Metodiev et al. (2016) [13] HSD17B10 NAD(P)(H)-dependent Global developmental delay, Early childhood AR 300256 Oerum et al. (2017) [14], (MRPP2) short-chain epilepsy, and cardiac involvement Falk et al. (2016) [15] dehydrogenase/reductases ELAC2 RNase Z Hypertrophic cardiomyopathy, Early childhood AR 605367 Haack et al. (2013) [16], hypotonia, lactic acidosis, delayed Shinwari et al. (2017) [17], psychomotor development Akawi et al. (2016) [18] FASTKD2 fas activated serine-threonine Later onset, milder MELAS Childhood AR 612322 Ghezzi et al. (2008) [19], kinase domain 2 protein (mitochondrial Yoo et al. 2017 [20] encephalomyopathy, lactic acidosis and stroke-like episode)-like syndrome with seizures, stroke-like episodes and optic atrophy. Mitochondrial encephalomyopathy with developmental delay, hemiplegia, convulsions, asymmetrical brain atrophy MTPAP Mitochondrial poly-A Progressive spastic ataxia with Juvenile or early AR 613672 Crosby et al. (2010) [21] polymerase optic atrophy childhood LRPPRC Leucine-rich PPR-motif Leigh syndrome French–Canadian Infantile AR 220111 Mootha et al. (2003) [22], containing protein variant (LSFC) Olahova et al. (2015) [23], Han et al. (2017) [24] OMIM, Online Mendelian Inheritance in Man; AR, autosomal recessive. Ithasbeenimplicated that TFAM-mediated alterations may be an important mechanism in neurodegeneration in Alzheimer, Huntington, Parkinson, and other neurodegenerative diseases [13].Becausealtered TFAM and mtDNA levelshavebeendetected in multiplemodelsofneurodegeneration, we suggest that the regulation of TFAM may be akeymechanismindisease pathomechanism or progression [13]. Maturation of the primary transcript: pre-RNA processing Transcription of the mitochondrial genome generates large polycistronic transcripts punctuated by the 22 mt-tRNAs that are conventionallycleaved by the RNase P-complex and the RNase Z activity of ELAC2at5 and 3 ends, respec- tively(Table 1)[5,6]. TRMT10C/MRPP1 Mutations in TRMT10C (encoding the mitochondrial RNase P protein 1 (MRPP1)) were reported in infants present- ing at birth with lactic acidosis,hypotonia,feeding difficulties, anddeafness [13].Bothindividuals died at 5 months after respiratory failure. MRPP1,along with MRPP2 andMRPP3, form the mitochondrial ribonuclease P (mt-RNase P) complex that cleaves the 5 endsofmt-tRNAs from polycistronic precursor transcripts. Analyses of fibroblasts from affected individualsharboringTRMT10C missense