Mitochondrial DNA Transcription and Its Regulation: An Evolutionary Perspective

Unlike the traditionally held view, mtDNA transcription is regulated not only by dedicated factors but also by known regulators of nuclear transcription. This suggests that although mtDNA transcription regulatory system is separated in space from the nucleus, the prokaryotic progenitor of mitochondria adapted to its host regulatory environment so as to enable coregulation. mtDNA transcriptional regulatory elements are not confined to noncoding regions and may also reside within genes. Hence, extensive mtDNA rearrangements, such as insertions, deletions, and inversions that occurred during the course of evolution, would have altered orientation of such elements and may affect transcription. Although mtDNA transcriptional regulation in mammals resembles that of humans, it can diverge considerably elsewhere. The bacterial heritage of mitochondria, as well as its independent genome [mitochondrial DNA (mtDNA)] and polycistronic transcripts, led to the view that mitochondrial transcriptional regulation relies on an evolutionarily conserved, prokaryotic-like system that is separated from the rest of the cell. Indeed, mtDNA transcription was previously thought to be governed by a few dedicated direct regulators, namely, the mitochondrial RNA polymerase (POLRMT), two transcription factors (TFAM and TF2BM), one transcription elongation (TEFM), and one known transcription termination factor (mTERF1). Recent findings have, however, revealed that known nuclear gene expression regulators are also involved in mtDNA transcription and have identified novel transcriptional features consistent with adaptation of the mitochondria to the regulatory environment of the precursor of the eukaryotic cell. Finally, whereas mammals follow the human mtDNA transcription pattern, other organisms notably diverge in terms of mtDNA transcriptional regulation. Hence, mtDNA transcriptional regulation is likely more evolutionary diverse than once thought. The bacterial heritage of mitochondria, as well as its independent genome [mitochondrial DNA (mtDNA)] and polycistronic transcripts, led to the view that mitochondrial transcriptional regulation relies on an evolutionarily conserved, prokaryotic-like system that is separated from the rest of the cell. Indeed, mtDNA transcription was previously thought to be governed by a few dedicated direct regulators, namely, the mitochondrial RNA polymerase (POLRMT), two transcription factors (TFAM and TF2BM), one transcription elongation (TEFM), and one known transcription termination factor (mTERF1). Recent findings have, however, revealed that known nuclear gene expression regulators are also involved in mtDNA transcription and have identified novel transcriptional features consistent with adaptation of the mitochondria to the regulatory environment of the precursor of the eukaryotic cell. Finally, whereas mammals follow the human mtDNA transcription pattern, other organisms notably diverge in terms of mtDNA transcriptional regulation. Hence, mtDNA transcriptional regulation is likely more evolutionary diverse than once thought. the animal kingdom can be divided according to those whose body plan presents longitudinal symmetry (i.e., bilaterians) and those lacking such a plan (non-bilaterians). The body plan of bilaterians comprises a head and tail, as well as a back and a belly. As such, they also present left and right sides. Non-bilaterians include, among others, organisms with radial symmetry, such as sea urchins and anemones. the displacement loop (D-loop) comprises the largest mtDNA noncoding region in mammals (∼1100 nucleotides) and harbors most of the known mtDNA replication and transcription regulatory elements. global run-on transcription with deep sequencing (GRO-seq), and its improved version, entitled precision run-on transcription (PRO-seq) are deep sequencing techniques designed to capture and sequence genome-wide nascent RNA transcripts in cells and tissue samples. The techniques are based on labeling nascent transcripts (usually by biotin), followed by capture, cDNA preparation, sequencing library preparation, and sequencing by the common deep sequencing platforms. an acronym for insertion and deletion mutations.