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Free keywords:
Animals
Cytochrome-c Oxidase Deficiency/*genetics
DNA, Mitochondrial/genetics
Electron Transport Complex IV/analysis
HeLa Cells
Humans
Leigh Disease/*genetics
Macromolecular Substances
Mice
Mice, Knockout
Mitochondria, Heart/*physiology
Neoplasm Proteins/deficiency/genetics/*physiology
Organ Specificity
Polyadenylation/*physiology
Polynucleotide Adenylyltransferase
Protein Biosynthesis/*physiology
RNA Stability
RNA, Messenger
RNA-Binding Proteins/metabolism
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.
