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LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs.

ABSTRACT: Regulation of mtDNA expression is critical for maintaining cellular energy homeostasis and may, in principle, occur at many different levels. The leucine-rich pentatricopeptide repeat containing (LRPPRC) protein regulates mitochondrial mRNA stability and an amino-acid substitution of this protein causes the French-Canadian type of Leigh syndrome (LSFC), a neurodegenerative disorder characterized by complex IV deficiency. We have generated conditional Lrpprc knockout mice and show here that the gene is essential for embryonic development. Tissue-specific disruption of Lrpprc in heart causes mitochondrial cardiomyopathy with drastic reduction in steady-state levels of most mitochondrial mRNAs. LRPPRC forms an RNA-dependent protein complex that is necessary for maintaining a pool of non-translated mRNAs in mammalian mitochondria. Loss of LRPPRC does not only decrease mRNA stability, but also leads to loss of mRNA polyadenylation and the appearance of aberrant mitochondrial translation. The translation pattern without the presence of LRPPRC is misregulated with excessive translation of some transcripts and no translation of others. Our findings point to the existence of an elaborate machinery that regulates mammalian mtDNA expression at the post-transcriptional level.

SUBMITTER: Ruzzenente B

PROVIDER: S-EPMC3261557 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs.

Ruzzenente Benedetta B Metodiev Metodi D MD Wredenberg Anna A Bratic Ana A Park Chan Bae CB Cámara Yolanda Y Milenkovic Dusanka D Zickermann Volker V Wibom Rolf R Hultenby Kjell K Erdjument-Bromage Hediye H Tempst Paul P Brandt Ulrich U Stewart James B JB Gustafsson Claes M CM Larsson Nils-Göran NG

The EMBO journal 20111101 2

Regulation of mtDNA expression is critical for maintaining cellular energy homeostasis and may, in principle, occur at many different levels. The leucine-rich pentatricopeptide repeat containing (LRPPRC) protein regulates mitochondrial mRNA stability and an amino-acid substitution of this protein causes the French-Canadian type of Leigh syndrome (LSFC), a neurodegenerative disorder characterized by complex IV deficiency. We have generated conditional Lrpprc knockout mice and show here that the g ...[more]

PMID: 22045337

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Project description:BackgroundGenes encoded in vertebrate mitochondrial DNAs are transcribed as a polycistronic transcript for both strands, which is later processed into individual mRNAs, rRNAs and tRNAs, followed by modifications, such as polyadenylation at the 3' end of mRNAs. Although mechanisms of the mitochondrial transcription and RNA processing have been extensively studied using some model organisms, structural variability of mitochondrial mRNAs across different groups of vertebrates is poorly understood. We conducted the high-throughput RNA sequencing to identify major polyadenylation sites for mitochondrial mRNAs in the Japanese grass lizard, Takydromus tachydromoides and compared the polyadenylation profiles with those identified similarly for 23 tetrapod species, featuring sauropsid taxa (reptiles and birds).ResultsAs compared to the human, a major polyadenylation site for the NADH dehydrogenase subunit 5 mRNA of the grass lizard was located much closer to its stop codon, resulting in considerable truncation of the 3' untranslated region for the mRNA. Among the other sauropsid taxa, several distinct polyadenylation profiles from the human counterpart were found for different mRNAs. They included various truncations of the 3' untranslated region for NADH dehydrogenase subunit 5 mRNA in four taxa, bird-specific polyadenylation of the light-strand-transcribed NADH dehydrogenase subunit 6 mRNA, and the combination of the ATP synthase subunit 8/6 mRNA with a neighboring mRNA into a tricistronic mRNA in the side-necked turtle Pelusios castaneus. In the last case of P. castaneus, as well as another example for NADH dehydrogenase subunit 1 mRNAs of some birds, the association between the polyadenylation site change and the gene overlap was highlighted. The variations in the polyadenylation profile were suggested to have arisen repeatedly in diverse sauropsid lineages. Some of them likely occurred in response to gene rearrangements in the mitochondrial DNA but the others not.ConclusionsThese results demonstrate structural variability of mitochondrial mRNAs in sauropsids. The efficient and comprehensive characterization of the mitochondrial mRNAs will contribute to broaden our understanding of their structural and functional evolution.

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LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs.

Publications

LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs.

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