Limits...
Mitochondrial transcript maturation and its disorders.

Van Haute L, Pearce SF, Powell CA, D'Souza AR, Nicholls TJ, Minczuk M - J. Inherit. Metab. Dis. (2015)

Bottom Line: Additionally, mutations in mtDNA-encoded genes may also affect RNA maturation and are frequently associated with human disease.We review the current knowledge on a subset of nuclear-encoded genes coding for proteins involved in mitochondrial RNA maturation, for which genetic variants impacting upon mitochondrial pathophysiology have been reported.Also, primary pathological mtDNA mutations with recognised effects upon RNA processing are described.

View Article: PubMed Central - PubMed

Affiliation: MRC Mitochondrial Biology Unit, Hills Road, Cambridge, CB2 0XY, UK.

ABSTRACT
Mitochondrial respiratory chain deficiencies exhibit a wide spectrum of clinical presentations owing to defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mitochondrial DNA (mtDNA) or mutations in nuclear genes coding for mitochondrially-targeted proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial biology including expression of mtDNA-encoded genes. Expression of the mitochondrial genes is extensively regulated at the post-transcriptional stage and entails nucleolytic cleavage of precursor RNAs, RNA nucleotide modifications, RNA polyadenylation, RNA quality and stability control. These processes ensure proper mitochondrial RNA (mtRNA) function, and are regulated by dedicated, nuclear-encoded enzymes. Recent growing evidence suggests that mutations in these nuclear genes, leading to incorrect maturation of RNAs, are a cause of human mitochondrial disease. Additionally, mutations in mtDNA-encoded genes may also affect RNA maturation and are frequently associated with human disease. We review the current knowledge on a subset of nuclear-encoded genes coding for proteins involved in mitochondrial RNA maturation, for which genetic variants impacting upon mitochondrial pathophysiology have been reported. Also, primary pathological mtDNA mutations with recognised effects upon RNA processing are described.

No MeSH data available.


Related in: MedlinePlus

Polycistronic transcription units in mitochondria. Polycistronic precursor mitochondrial transcripts are shown. The transcript from LSP contains only the coding sequences for the ND6 subunit of complex I and eight mt-tRNAs. All other coding sequences are produced by transcription from HSP. With some exceptions (triangles), mt-rRNAs (blue) and mt-mRNAs (red) are punctuated with mt-tRNAs (green). The endonucleolytic processing of mt-tRNA liberates most of the mt-mRNAs and the two mt-rRNAs. The enzymatic machinery responsible for the processing at the non-canonical sites, not punctuated with mt-tRNAs, is not well investigated. ND6 mRNA shows multiple 3′ ends: either 500 nt (Slomovic et al 2005) or 30 nt (Mercer et al 2011) downstream of the translation termination codon
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4493943&req=5

Fig3: Polycistronic transcription units in mitochondria. Polycistronic precursor mitochondrial transcripts are shown. The transcript from LSP contains only the coding sequences for the ND6 subunit of complex I and eight mt-tRNAs. All other coding sequences are produced by transcription from HSP. With some exceptions (triangles), mt-rRNAs (blue) and mt-mRNAs (red) are punctuated with mt-tRNAs (green). The endonucleolytic processing of mt-tRNA liberates most of the mt-mRNAs and the two mt-rRNAs. The enzymatic machinery responsible for the processing at the non-canonical sites, not punctuated with mt-tRNAs, is not well investigated. ND6 mRNA shows multiple 3′ ends: either 500 nt (Slomovic et al 2005) or 30 nt (Mercer et al 2011) downstream of the translation termination codon

Mentions: Transcription of the human mitochondrial genome occurs on both DNA strands, is polycistronic, and produces long transcripts of mt-mRNAs and mt-rRNAs, usually interspersed with mt-tRNAs (Ojala et al 1981). Transcription of the light strand (L-strand, Fig. 1) template occurs from a single promoter (L-strand promoter, LSP) and this long transcript encodes the ND6 gene and eight mt-tRNAs (Figs. 1 and 3) (Montoya et al 1982, 1983). The majority of initiation events from LSP are believed to terminate some 200 bases downstream from the promoter, at “conserved sequence block 2” (CSB2) (Wanrooij et al 2010). This short RNA species is used to prime replication of the heavy DNA strand (H-strand, Fig. 1) as well as the synthesis of the D-loop, whose biogenesis and function is discussed in our recent review (Nicholls and Minczuk 2014). Classically, transcription of the H-strand template is initiated from two sites (H-strand promoter 1 and 2, HSP1 and HSP2), located approximately 100 bases apart in the non-coding region (NCR) (Montoya et al 1982, 1983; Chang and Clayton 1984). HSP1 is located just upstream of the mt-tRNAPhe gene, and initiation from this site produces a short transcript consisting of the two ribosomal RNAs (12S and 16S) and mt-tRNAVal, terminating at the mt-tRNALeu(UUR) gene. Transcription from HSP2, immediately upstream from the 12S mt-rRNA gene, bypasses this termination and produces an almost genome-length transcript of 2 mt-rRNAs, 12 mt-mRNAs and 14 mt-tRNAs. The mitochondrial transcription termination factor mTERF1 binds strongly to a tridecamer DNA sequence and has been proposed to terminate H-strand transcription at the mt-tRNALeu(UUR) gene (Christianson and Clayton 1988; Kruse et al 1989; Fernandez-Silva et al 1997). However, this was brought into doubt by the discovery that a mouse knockout of mTERF1 had normal H-strand transcription (Terzioglu et al 2013). It has been suggested that mTERF1 may actually serve to terminate the L-strand transcript, preventing the formation of antisense mt-rRNA species. The existence of HSP2 as a functional promoter in vivo is also questionable as transcription from this site is not readily detectable using established in vitro transcription systems (Litonin et al 2010). It may be the case, therefore, that only LSP and HSP1 (indicated as HSP on Fig. 1) are responsible for the transcription of all mitochondrially-encoded transcripts.


Mitochondrial transcript maturation and its disorders.

Van Haute L, Pearce SF, Powell CA, D'Souza AR, Nicholls TJ, Minczuk M - J. Inherit. Metab. Dis. (2015)

Polycistronic transcription units in mitochondria. Polycistronic precursor mitochondrial transcripts are shown. The transcript from LSP contains only the coding sequences for the ND6 subunit of complex I and eight mt-tRNAs. All other coding sequences are produced by transcription from HSP. With some exceptions (triangles), mt-rRNAs (blue) and mt-mRNAs (red) are punctuated with mt-tRNAs (green). The endonucleolytic processing of mt-tRNA liberates most of the mt-mRNAs and the two mt-rRNAs. The enzymatic machinery responsible for the processing at the non-canonical sites, not punctuated with mt-tRNAs, is not well investigated. ND6 mRNA shows multiple 3′ ends: either 500 nt (Slomovic et al 2005) or 30 nt (Mercer et al 2011) downstream of the translation termination codon
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4493943&req=5

Fig3: Polycistronic transcription units in mitochondria. Polycistronic precursor mitochondrial transcripts are shown. The transcript from LSP contains only the coding sequences for the ND6 subunit of complex I and eight mt-tRNAs. All other coding sequences are produced by transcription from HSP. With some exceptions (triangles), mt-rRNAs (blue) and mt-mRNAs (red) are punctuated with mt-tRNAs (green). The endonucleolytic processing of mt-tRNA liberates most of the mt-mRNAs and the two mt-rRNAs. The enzymatic machinery responsible for the processing at the non-canonical sites, not punctuated with mt-tRNAs, is not well investigated. ND6 mRNA shows multiple 3′ ends: either 500 nt (Slomovic et al 2005) or 30 nt (Mercer et al 2011) downstream of the translation termination codon
Mentions: Transcription of the human mitochondrial genome occurs on both DNA strands, is polycistronic, and produces long transcripts of mt-mRNAs and mt-rRNAs, usually interspersed with mt-tRNAs (Ojala et al 1981). Transcription of the light strand (L-strand, Fig. 1) template occurs from a single promoter (L-strand promoter, LSP) and this long transcript encodes the ND6 gene and eight mt-tRNAs (Figs. 1 and 3) (Montoya et al 1982, 1983). The majority of initiation events from LSP are believed to terminate some 200 bases downstream from the promoter, at “conserved sequence block 2” (CSB2) (Wanrooij et al 2010). This short RNA species is used to prime replication of the heavy DNA strand (H-strand, Fig. 1) as well as the synthesis of the D-loop, whose biogenesis and function is discussed in our recent review (Nicholls and Minczuk 2014). Classically, transcription of the H-strand template is initiated from two sites (H-strand promoter 1 and 2, HSP1 and HSP2), located approximately 100 bases apart in the non-coding region (NCR) (Montoya et al 1982, 1983; Chang and Clayton 1984). HSP1 is located just upstream of the mt-tRNAPhe gene, and initiation from this site produces a short transcript consisting of the two ribosomal RNAs (12S and 16S) and mt-tRNAVal, terminating at the mt-tRNALeu(UUR) gene. Transcription from HSP2, immediately upstream from the 12S mt-rRNA gene, bypasses this termination and produces an almost genome-length transcript of 2 mt-rRNAs, 12 mt-mRNAs and 14 mt-tRNAs. The mitochondrial transcription termination factor mTERF1 binds strongly to a tridecamer DNA sequence and has been proposed to terminate H-strand transcription at the mt-tRNALeu(UUR) gene (Christianson and Clayton 1988; Kruse et al 1989; Fernandez-Silva et al 1997). However, this was brought into doubt by the discovery that a mouse knockout of mTERF1 had normal H-strand transcription (Terzioglu et al 2013). It has been suggested that mTERF1 may actually serve to terminate the L-strand transcript, preventing the formation of antisense mt-rRNA species. The existence of HSP2 as a functional promoter in vivo is also questionable as transcription from this site is not readily detectable using established in vitro transcription systems (Litonin et al 2010). It may be the case, therefore, that only LSP and HSP1 (indicated as HSP on Fig. 1) are responsible for the transcription of all mitochondrially-encoded transcripts.

Bottom Line: Additionally, mutations in mtDNA-encoded genes may also affect RNA maturation and are frequently associated with human disease.We review the current knowledge on a subset of nuclear-encoded genes coding for proteins involved in mitochondrial RNA maturation, for which genetic variants impacting upon mitochondrial pathophysiology have been reported.Also, primary pathological mtDNA mutations with recognised effects upon RNA processing are described.

View Article: PubMed Central - PubMed

Affiliation: MRC Mitochondrial Biology Unit, Hills Road, Cambridge, CB2 0XY, UK.

ABSTRACT
Mitochondrial respiratory chain deficiencies exhibit a wide spectrum of clinical presentations owing to defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mitochondrial DNA (mtDNA) or mutations in nuclear genes coding for mitochondrially-targeted proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial biology including expression of mtDNA-encoded genes. Expression of the mitochondrial genes is extensively regulated at the post-transcriptional stage and entails nucleolytic cleavage of precursor RNAs, RNA nucleotide modifications, RNA polyadenylation, RNA quality and stability control. These processes ensure proper mitochondrial RNA (mtRNA) function, and are regulated by dedicated, nuclear-encoded enzymes. Recent growing evidence suggests that mutations in these nuclear genes, leading to incorrect maturation of RNAs, are a cause of human mitochondrial disease. Additionally, mutations in mtDNA-encoded genes may also affect RNA maturation and are frequently associated with human disease. We review the current knowledge on a subset of nuclear-encoded genes coding for proteins involved in mitochondrial RNA maturation, for which genetic variants impacting upon mitochondrial pathophysiology have been reported. Also, primary pathological mtDNA mutations with recognised effects upon RNA processing are described.

No MeSH data available.


Related in: MedlinePlus