title: 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.
authors: Department of Mitochondrial Genetics, Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors: Benedetta
authors: B
authors: Ruzzenente
authors: Metodi D
authors: MD
authors: Metodiev
authors: Anna
authors: A
authors: Wredenberg
authors: Ana
authors: A
authors: Bratic
authors: Chan Bae
authors: CB
authors: Park
authors: Yolanda
authors: Y
authors: Cámara
authors: Dusanka
authors: D
authors: Milenkovic
authors: Volker
authors: V
authors: Zickermann
authors: Rolf
authors: R
authors: Wibom
authors: Kjell
authors: K
authors: Hultenby
authors: Hediye
authors: H
authors: Erdjument-Bromage
authors: Paul
authors: P
authors: Tempst
authors: Ulrich
authors: U
authors: Brandt
authors: James B
authors: JB
authors: Stewart
authors: Claes M
authors: CM
authors: Gustafsson
authors: Nils-Göran
authors: NG
authors: Larsson
mesh_terms: D000818:Animals; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics; D003576:Electron Transport Complex IV / Q000032:analysis; D006367:HeLa Cells; D006801:Humans; D007888:Leigh Disease / Q000235:genetics*; D046911:Macromolecular Substances; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000502:physiology*; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009928:Organ Specificity; D026723:Polyadenylation / Q000502:physiology*; D011062:Polynucleotide Adenylyltransferase; D014176:Protein Biosynthesis / Q000502:physiology*; D020871:RNA Stability; D012333:RNA, Messenger; D016601:RNA-Binding Proteins / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; C486222:Lrpprc protein, mouse; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C544451:SLIRP protein, mouse; D003576:Electron Transport Complex IV; D011062:Polynucleotide Adenylyltransferase