LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria

Mutations in LRPPRC are responsible for the French Canadian variant of Leigh syndrome (LSFC), a neurodegenerative disorder caused by a tissue-specific deficiency in cytochrome c oxidase (COX). To investigate the pathogenic mechanism of disease, we studied LRPPRC function in LSFC and control fibrobla...

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Published in:Molecular biology of the cell 2010-04, Vol.21 (8), p.1315-1323
Main Authors: Sasarman, Florin, Brunel-Guitton, Catherine, Antonicka, Hana, Wai, Timothy, Shoubridge, Eric A
Format: Article
Language:English
Subjects:
Electron Transport Complex IV - metabolism
Fibroblasts - enzymology
Fibroblasts - pathology
Gene Expression Regulation
Humans
Kinetics
Leigh Disease - enzymology
Leigh Disease - genetics
Leigh Disease - pathology
Mitochondria - genetics
Mitochondria - pathology
Molecular Weight
Multiprotein Complexes - metabolism
Mutant Proteins - metabolism
Neoplasm Proteins - metabolism
Oxidative Phosphorylation
Protein Binding
Protein Transport
Ribonucleoproteins - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA-Binding Proteins - metabolism
Transcription, Genetic
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Summary:Mutations in LRPPRC are responsible for the French Canadian variant of Leigh syndrome (LSFC), a neurodegenerative disorder caused by a tissue-specific deficiency in cytochrome c oxidase (COX). To investigate the pathogenic mechanism of disease, we studied LRPPRC function in LSFC and control fibroblasts. The level of mutated LRPPRC is reduced in LSFC cells, and this results in decreased steady-state levels of most mitochondrial mRNAs, but not rRNAs or tRNAs, a phenotype that can be reproduced by siRNA-mediated knockdown of LRPPRC in control cells. Processing of the primary transcripts appears normal. The resultant defect in mitochondrial protein synthesis in LSFC cells disproportionately affects the COX subunits, leading to an isolated COX assembly defect. Further knockdown of LRPPRC produces a generalized assembly defect in all oxidative phosphorylation complexes containing mtDNA-encoded subunits, due to a severe decrease in all mitochondrial mRNAs. LRPPRC exists in a high-molecular-weight complex, and it coimmunoprecipitates with SLIRP, a stem-loop RNA-binding protein. Although this interaction does not depend on mitochondrial mRNA, both proteins show reduced stability in its absence. These results implicate LRPPRC in posttranscriptional mitochondrial gene expression as part of a ribonucleoprotein complex that regulates the stability and handling of mature mRNAs.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E10-01-0047