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