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The Transcription Machinery in Mammalian Mitochondria

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The Transcription Machinery in Mammalian Mitochondria View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1659 (2004) 148–152 http://www.elsevier.com/locate/bba Review The transcription machinery in mammalian mitochondria Martina Gasparia,b, Nils-Gfran Larssona,b, Claes M. Gustafssona,* aDepartment of Medical Nutrition, Karolinska Institute, Novum, SE-141 86 Stockholm, Sweden bDepartment of Biosciences, Karolinska Institute, Novum, SE-141 86 Stockholm, Sweden Received 5 July 2004; received in revised form 18 October 2004; accepted 19 October 2004 Available online 27 October 2004 Abstract Initiation of transcription at mitochondrial promoters in mammalian cells requires the simultaneous presence of a monomeric mitochondrial RNA polymerase, mitochondrial transcription factor A, and either transcription factor B1 or B2. We here review recent progress in our understanding of how these basal factors cooperate in the initiation and regulation of mitochondrial transcription. We describe the evolutionary origin of individual transcription factors and discuss how these phylogenetic relationships may facilitate a molecular understanding of the mitochondrial transcription machinery. D 2004 Elsevier B.V. All rights reserved. Keywords: POLRMT; TFAM; TFB2M; Mitochondrion; Transcription 1. Introduction produces RNA species spanning the rDNA region, i.e., the genes for the two mitochondrial rRNAs and ending at the Thirteen of the ~80 different proteins present in the border between the 16 S rRNA and the tRNALeu(UUR) respiratory chain of human mitochondria are encoded by the genes [4–6]. The existence of such a separate transcription mitochondrial genome (mtDNA). The circular mtDNA, unit may explain why the steady-state levels of rRNAs are which is present in 1000 to 10000 copies in the human cell, much higher than the steady-state levels of mRNAs (see also encodes for two ribosomal RNAs, and 22 transfer below). RNAs. The compact 16.6-kbp genome lacks introns and the Phylogenetic analyses of the mitochondrial genome only longer non-coding region contains the control elements (mtDNA) suggests that the mitochondrion originates from for transcription and replication of mtDNA [1]. The two an a-protobacterium, which early in evolution developed a mtDNA strands differ in their G+T content and can symbiotic relationship with a primitive eukaryotic cell [7]. therefore be separated on denaturing cesium chloride During the course of time, ancestral bacterial genes have gradients into a heavy strand (H-strand) and a light strand been transferred from the mitochondrial to the nuclear (L-strand). In human cells, each strand contains one single genome, as is evident from the presence of orthologous promoter for transcriptional initiation, the light-strand genes in the mitochondrial genome in some species and in promoter (LSP) or the heavy-strand promoter (HSP). the nuclear genome of other species. Gene transfer explains Transcription from the mitochondrial promoters produces why all proteins necessary for mtDNA replication, as well polycistronic precursor RNA encompassing all the genetic as transcription and translation of mtDNA-encoded genes, information encoded in each of the specific strands, and the are encoded by the nuclear genome. It is, however, an open primary transcripts are processed to produce the individual question why mitochondria have retained these elaborate tRNA and mRNA molecules [2,3]. There is likely also a enzymatic machineries to replicate and express a separate second initiation site for heavy strand transcription, which genome containing only a few genes [8]. It has been argued that some hydrophobic proteins are difficult to import across * Corresponding author. Tel.: +46 8 58583974; fax: + 46 8 7116659. the mitochondrial membranes and sort to the correct E-mail address: [email protected] (C.M. Gustafsson). location, and that these proteins therefore need to be 0005-2728/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbabio.2004.10.003 M. Gaspari et al. / Biochimica et Biophysica Acta 1659 (2004) 148–152 149 produced within the mitochondrion [9,10]. In support of this TFB1M and TFB2M display primary sequence similarity notion, the genes conserved in every completely sequenced to a family of rRNA methyltransferases, which dimethylates mitochondrial genome, cox1 and cob, are also among the two adjacent adenosine bases near the 3V end of the small most hydrophobic of all proteins present in the mitochond- subunit rRNA during ribosome biogenesis. Human TFB1M rion [11]. Another explanation could be the differences in is in fact a dual function protein, which not only supports codon usage between the nuclear and mitochondrial mitochondrial transcription in vitro, but also acts as a rRNA genomes, which makes further gene transfer from the methyltransferase [20]. The methyltransferase activity is not mitochondrion difficult. We favor a third explanation, which required for transcription, since point mutations in con- suggests that the regulated expression of mitochondrial served methyltransferase motifs of TFB1M revealed that it genes is important for metabolic control in eukaryotic cells stimulates transcription in vitro independently of S-adeno- [12]. The molecular machines governing mitochondrial sylmethionine binding and rRNA methyltransferase activity. gene expression may be directly influenced by the Although primary sequence similarities between yeast components of the respiratory chain and the redox state of mt-TFB and rRNA methyltransferases are limited, X-ray the mitochondrion. There is experimental support for an structure of mt-TFB revealed a striking homology to the E. analogous model in plants, where there is a rapid and direct coli rRNA methyltransferase ErmCV [21]. It is therefore redox control of chloroplast transcription [13]. possible that an rRNA dimethyltransferase was recruited to the mitochondrial transcription machinery early in evolu- tion, but that the original methyltransferase activity has been 2. Mitochondrial transcription lost in S. cerevisiae. In support of this notion, the dimethyltransferase modification is universally conserved Human mtDNA is transcribed by a dedicated mitochon- in prokaryotes and eukaryotes, with the only known drial RNA polymerase (POLRMT), which displays signifi- exception being S. cerevisiae mitochondrial 12S rRNA cant sequence similarity to the monomeric RNA [22]. The relative importance of TFB1M and TFB2M in polymerases found in bacteriophages [14]. In contrast to mitochondrial transcription and rRNA methylation remains the phage T7 RNA polymerase, POLRMT cannot interact to be established. It is possible that TFB1M is responsible with promoter DNA and initiate transcription on its own, for the dimethylation of the small subunit rRNA during but requires the simultaneous presence of a high mobility ribosome biogenesis, whereas TFB2M has lost the methyl- group-box protein (mitochondrial transcription factor A; transferase activity and evolved into a specialized tran- TFAM), and either transcription factor B1 (TFB1M) or B2 scription factor. Even if the recruitment of an RNA (TFB2M) [15]. The four proteins of the basal mitochondrial modifying enzyme to the mitochondrial transcription transcription machinery have been purified in recombinant machinery is surprising, it is not without precedent. The form and used to reconstitute transcription in vitro with a smaller h subunit of the mitochondrial DNA polymerase is promoter-containing DNA fragment [16]. Although both structurally homologous to a family of tRNA synthetases TFB1M and TFB2M can support in vitro transcription with [23]. POLRMT, TFB2M is at least two orders of magnitude more The yeast mitochondrial RNA polymerase contains a active than TFB1M. unique amino-terminal extension, which is absent in The transcription machinery in budding yeast appears homologous bacteriophage RNA polymerases. The function less complicated, since it only contains one single TFB1M/ of the amino-terminal extension is separable from the TFB2M homologue, which is denoted mt-TFB or Mtf1. known RNA polymerization activity of the enzyme [24]. The S. cerevisiae mitochondrial RNA polymerase (Rpo41) A deletion of 185 N-terminal amino acids of the S. and mt-TFB form a heterodimer that recognizes mitochon- cerevisiae RNA polymerase results in a temperature- drial promoters and initiate transcription [17,18]. The sensitive mitochondrial petite phenotype, characterized by importance of the heterodimer is underscored by the recent increased instability and eventual loss of the mitochondrial identification of an Rpo41 mutant (E1224A), which genome. Mitochondrial transcription initiation in vivo is displayed reduced interactions with mt-TFB in a two- largely unaffected by this mutation and expression of just hybrid assay [19]. Although the E1224A mutant had full the amino-terminal portion of the protein in trans partially activity in a non-selective in vitro transcription assay, it suppresses the mitochondrial defect, indicating that the was temperature-sensitive for selective transcription from amino-terminal extension of the enzyme harbors an inde- linear DNA templates containing specific mitochondrial pendent functional domain that is required for mtDNA promoters. In agreement with the observations in budding replication and/or stability. In support of this notion, the yeast, both TFB1M and TFB2M can form a heterodimeric domain interacts specifically with Nam1, a protein
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