LRPPRC (leucine-rich pentatricopeptide repeat-containing) has been shown to be essential for the maturation of COX (cytochrome c oxidase), possibly by stabilizing RNA transcripts of COXI, COXII and COXIII genes encoded in mtDNA (mitochondrial DNA). We established a mouse ‘gene-trap’ model using ES cells (embryonic stem cells) in which the C-terminus of LRPPRC has been replaced with a β-geo construct. Mice homozygous for this modification were found to be subject to embryonic lethality, with death before 12.5 dpc (days post-coitum). Biochemical analysis of MEFs (mouse embryonic fibroblasts) isolated from homozygous mutants showed a major decrease in COX activity, with slight reductions in other respiratory chain complexes with mtDNA encoded components. Constructs of LRPPRC containing different numbers of PPRs (pentatricopeptide repeats) were expressed as recombinant proteins and tested for their ability to bind to the COXI mRNA transcript. Full binding required the first 19 PPR motifs. A specific segment of COXI mRNA was identified as the binding target for LRPPRC, encoded by mouse mtDNA nucleotides 5961–6020. These data strongly suggest that LRPPRC is involved in the maturation of COX, and is involved in stabilizing of mitochondrial mRNAs encoding COX transcripts.
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Research Article|
December 14 2011
LRPPRC mutation suppresses cytochrome oxidase activity by altering mitochondrial RNA transcript stability in a mouse model
Fenghao Xu;
Fenghao Xu
*Genetics and Genome Biology, The Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8
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Jane B. L. Addis;
Jane B. L. Addis
*Genetics and Genome Biology, The Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8
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Jessie M. Cameron;
Jessie M. Cameron
*Genetics and Genome Biology, The Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8
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Brian H. Robinson
Brian H. Robinson
1
*Genetics and Genome Biology, The Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8
†Departments of Biochemistry and Paediatrics, University of Toronto, 1 King's College Circle, Toronto, ON, Canada M5S 1A8
1To whom correspondence should be addressed (email bhr@sickkids.ca).
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Publisher: Portland Press Ltd
Received:
June 01 2011
Revision Received:
August 17 2011
Accepted:
August 31 2011
Accepted Manuscript online:
August 31 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 441 (1): 275–283.
Article history
Received:
June 01 2011
Revision Received:
August 17 2011
Accepted:
August 31 2011
Accepted Manuscript online:
August 31 2011
Citation
Fenghao Xu, Jane B. L. Addis, Jessie M. Cameron, Brian H. Robinson; LRPPRC mutation suppresses cytochrome oxidase activity by altering mitochondrial RNA transcript stability in a mouse model. Biochem J 1 January 2012; 441 (1): 275–283. doi: https://doi.org/10.1042/BJ20110985
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