Mechanisms of mammalian mitochondrial transcription

Abstract

Numerous age-related human diseases have been associated with deficiencies in cellular energy production. Moreover, genetic alterations resulting in mitochondrial dysfunction are the cause of inheritable disorders commonly known as mitochondrial diseases. Many of these deficiencies have been directly or indirectly linked to deficits in mitochondrial gene expression. Transcription is an essential step in gene expression and elucidating the molecular mechanisms involved in this process is critical for understanding defects in energy production. For the past five decades, substantial efforts have been invested in the field of mitochondrial transcription. These efforts have led to the discovery of the main protein factors responsible for transcription as well as to a basic mechanistic understanding of the transcription process. They have also revealed various mechanisms of transcriptional regulation as well as the links that exist between the transcription process and downstream processes of RNA maturation. Here, we review the knowledge gathered in early mitochondrial transcription studies and focus on recent findings that shape our current understanding of mitochondrial transcription, posttranscriptional processing, as well as transcriptional regulation in mammalian systems.

Keywords: MTERF1; POLRMT; TEFM; TFAM; TFB2M; mitochondrial RNA processing; mitochondrial gene expression; mitochondrial transcription.

Figure 1

Organization of mitochondrial transcription. (a) Scheme of the mitochondrial genome indicating key functional loci as well as the different gene products. rRNAs (red) and most mRNAs (blue) are coded in the H‐strand, while a single mRNA (ND6; green) is coded by the L‐strand. tRNA genes are show in gray. (b) Scheme of the full‐length polycistronic mitochondrial transcripts indicating the gene products encoded by each transcript

Figure 2

Structures of the mitochondrial transcription machinery. (a) POLRMT (PDBID: 3SPA) adopts a canonical right‐hand fold with fingers, palm, and thumb subdomains. The POLRMT molecular surface is in transparent gray. The fingers are green, the thumb is dark green, the palm is light green, and the N‐terminal and PPR domains are blue. The DNA duplex is show in red‐orange. (b) TFAM (PDBID: 3TMM) is composed of two HMG box domains and is able to induce a 180° bend in the DNA. The TFAM molecular surface is transparent, the two HMG boxes (a and b) are shown in green, the linker is light blue and the C‐terminal tail (CTT) is blue. The DNA duplex backbone is shown in orange ribbon and the bases are represented in sticks. (c) The transcription initiation complex is formed by TFAM (blue), TFB2M (magenta), and POLRMT (gray). TFAM bends the DNA upstream of the transcription start site (red arrow) and recruits POLRMT. TFB2M binds the nontemplate strand and stabilizes the open promoter complex. (d) A TEFM dimer binds to the elongating POLRMT and acts as a sliding clamp, enhancing its processivity. The structure of an elongation complex (PDBID: 5OLA) is shown without (left) and with TEFM (right), highlighting how the TEFM dimer covers the upstream and downstream DNA duplex (orange) as well as the nascent RNA strand (red). (e) MTERF1 (PDBID: 3MVA) makes extensive contacts with the termination sequence and promotes unwinding of the DNA duplex and base‐flipping of three nucleotides, both bases of the A3243 base pair (mutated in MELAS39) as well as C3242

Figure 3

Overview of mammalian mitochondrial RNA processing. RNA processing is believed to take place co‐transcriptionally. Cleavage by RNases P and Z liberates individual mRNAs, tRNAs and rRNAs. These RNAs then undergo different modifications (see text) resulting in maturation and utilization in downstream processes (i.e., ribosome assembly and translation) or, alternatively, in degradation of unstable RNAs