Mitochondrial transcript maturation and its disorders

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.

Fig. 1

Genetic map of the mitochondrial genome. The organisation of the genes on human mitochondrial genome is shown. The two strands of the human mtDNA, denoted light (L-) and heavy (H-), code for 2 mt-rRNAs (blue), 22 mt-tRNAs (green) and 11 mt-mRNA molecules (red). The 11 mt-mRNAs encode 13 polypeptides of the electron transport chain and ATP synthase, where open reading frames of ATP8/ATP6 and ND4/ND4L overlap and are contained within bicistronic mRNAs. The main non-coding region (NCR) contains promoters for transcription of the H-strand and L-strand, HSP and LSP, respectively

Fig. 2

Mitochondrial RNA metabolism. The mitochondrial rRNAs (blue), mRNAs (red) and tRNAs (green) are transcribed from the L- and H-strands as polycistronic units that undergo endonucleolytic processing. Following the liberation of the individual mt-mRNA, mt-rRNA and mt-tRNA transcripts, they undergo post-transcriptional modifications. Several nucleotides of mt-rRNAs are modified to facilitate mitoribosome biogenesis and function. A poly(A) tail is added to mt-mRNAs, with the exception of the L-strand-encoded ND6. Mt-tRNAs undergo extensive post-transcriptional nucleotide modification, in addition to a CCA trinucleotide synthesis at the 3′ end, before being aminoacylated with a cognate amino acid. Decay and surveillance pathways have also been described for mammalian mtRNA

Fig. 3

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

Fig. 4

Post-transcriptional modifications of mitochondrial ribosomal RNA. Schematics of the secondary structure of 12S and 16S mt-rRNAs, indicating post-transcriptionally modified bases (circles) is shown. The details of the chemical modification and enzyme responsible (if known) for each mt-rRNA position is given in boxes, indicating the mt-rRNA base position number next to each box. The chemical modifications identified in mammalian species other than human are in brackets. Colour coding: blue, enzyme responsible for particular modification has been identified; grey, modifying enzyme has not been identified

Fig. 5

Post-transcriptional modifications of mitochondrial transfer RNA and human disease. Schematics of the “clover leaf” secondary structure of a generic mitochondrial tRNA indicating post-transcriptionally modified bases (circles) is shown. The details of the chemical modification and the enzyme responsible (if known) for each mt-tRNA position is given in boxes, indicating the mt-tRNA base position number next to each box. The chemical modifications identified in mammalian species other than human are in brackets. Colour coding: red, enzyme responsible for the modification has been associated with human disease; blue, enzyme responsible for particular modification has been identified; grey, modifying enzyme has not been identified

Fig. 6

Primary mtDNA mutation affecting mitochondrial RNA maturation. Schematics of the “clover leaf” secondary structure of a generic mitochondrial tRNA indicating the individual positions for which mutations that affect mt-tRNA maturation are described in one or multiple mt-tRNAs (see also Table 2). The “bold circles” show mutations in mt-tRNA^Leu(UUR) that affect mt-rRNA maturation as well as mt-tRNA maturation