Trends in Biochemical Sciences
ReviewMitochondrial transcription and its regulation in mammalian cells
Section snippets
The mitochondrial genome in mammalian cells
Human mitochondria contain a circular double-stranded DNA genome (mtDNA) of ∼16 600 base pairs (bp). The genome encodes two rRNAs, 22 tRNAs and 13 of the ∼90 different proteins present in the respiratory chain. The remaining components of the respiratory chain are encoded by nuclear genes and are imported to the mitochondrion via specialized import systems [1]. The genome lacks introns; the only long, non-coding region of the genome contains the control elements for transcription and
Mitochondrial RNA polymerase
The existence of a single subunit RNA polymerase (RNAP) in mitochondria was first reported in yeast 12, 13 and later in human cells [14]. The mitochondrial RNAP (mt-RNAP) from yeast (Rpo41) and human cells (POLRMT, also known as h-mtRPOL) display high sequence similarity to the C-terminal part of RNA polymerases encoded by the T-odd lineage of bacteriophages (e.g. T7 and T3) 14, 15. The mitochondrial RNA polymerases contain a unique N-terminal extension (Figure 2). In yeast, deletion of amino
Accessory factors needed for POLRMT function
The bacteriophage T7 RNAP interacts directly with promoter elements and can initiate transcription on its own. By contrast, POLRMT requires the assistance of mitochondrial transcription factor A (TFAM) and one of the mitochondrial transcription factor B paralogues, TFB1M or TFB2M.
TFAM contains two tandem high-mobility group (HMG) box domains separated by a 27-amino-acid residue-linker region and followed by a 25-residue C-terminal tail. Biochemical characterization of TFAM has revealed that the
Mechanisms of promoter recognition and transcription initiation
How the mammalian mitochondrial transcription machinery recognizes promoter sequences is not fully understood. POLRMT in complex with TFB1M or TFB2M cannot initiate transcription in the absence of TFAM. One possible role for TFAM might be to introduce specific structural alterations in mtDNA, for example, unwinding of the promoter region, which can facilitate transcription initiation [34]. The sequence-specific binding of a TFAM upstream of HSP and LSP might enable the protein to introduce
A nuclear isoform of POLRMT
Recent findings indicate that the gene encoding POLRMT specifies two single-polypeptide polymerases [termed single-polypeptide RNA polymerases-IV (spRNAP-IV)], one that is targeted to the mitochondria and one that has a function in the nucleus [40]. The nuclear spRNAP-IV lacks the N-terminal 262 amino acids that are present in the mitochondrial form and is produced via alternative splicing. This observation, therefore, indicates that the mitochondrial transcription machinery can directly
Regulation of transcriptional initiation
How mitochondrial transcription is regulated in response to the metabolic needs of the eukaryotic cell is largely unknown. In yeast, Rpo41 is involved in the coordinated control of nuclear and mitochondrial transcription. There is a direct correlation between in vivo changes in mitochondrial transcript abundance and in vitro sensitivity of mitochondrial promoters to ATP concentration [41]. It seems that the Rpo41 itself senses in vivo ATP levels and that shifting cellular pools of ATP might
Regulation of transcription termination
There are three mitochondrial transcription units (those starting at HSP1, HSP2 and LSP), but only the one starting at HSP1 has a clearly established termination site, which is located at the end of the 16S rRNA-encoding gene [3]. Transcription termination of the HSP1 unit at this site is widely believed to be mediated by mTERF, a 39-kDa protein that binds to a 28-bp region at the 3′ end of the tRNALeu(UUR) gene in a sequence-specific manner 49, 50. The mTERF protein can terminate transcription
Concluding remarks
The basal components of the mitochondrial transcription machinery are known, but the mechanisms of mitochondrial gene transcription are poorly understood. The close structural relationship that exists between POLRMT and the T7 RNAP, suggests that previous studies of phage transcription might prove essential for a molecular understanding of the mitochondrial transcription machinery. Furthermore, many regulatory aspects of mitochondrial transcription, including the question of how it is regulated
Acknowledgements
Space limitations have precluded the inclusion of many appropriate publications and we apologize to those authors. This work was supported by grants from the Swedish Research Council, the Swedish Cancer Society, European Commission (fp6 EUMITOCOMBAT) and the Swedish Foundation for Strategic Research. J.A-C. is a recipient of a Marie Curie Intra-European Fellowships from the European Commission (CEIF-CT-2005–011078).
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