Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

French Canadian Leigh Syndrome (LSFC) is an early-onset, progressive neurodegenerative disorder with a distinct pattern of tissue involvement. Most cases are caused by a founder missense mutation in LRPPRC. LRPPRC forms a ribonucleoprotein complex with SLIRP, another RNA-binding protein, and this stabilizes polyadenylated mitochondrial mRNAs. LSFC fibroblasts have reduced levels of LRPPRC and a specific complex IV assembly defect; however, further depletion of mutant LRPPRC results in a complete failure to assemble a functional oxidative phosphorylation system, suggesting that LRPPRC levels determine the nature of the biochemical phenotype. We tested this hypothesis in cultured muscle cells and tissues from LSFC patients. LRPPRC levels were reduced in LSFC muscle cells, resulting in combined complex I and IV deficiencies. A similar combined deficiency was observed in skeletal muscle. Complex IV was only moderately reduced in LSFC heart, but was almost undetectable in liver. Both of these tissues showed elevated levels of complexes I and III. Despite the marked biochemical differences, the steady-state levels of LRPPRC and mitochondrial mRNAs were extremely low, LRPPRC was largely detergent-insoluble, and SLIRP was undetectable in all LSFC tissues. The level of the LRPPRC/SLIRP complex appeared much reduced in control tissues by the first dimension blue-native polyacrylamide gel electrophoresis (BN-PAGE) analysis compared with fibroblasts, and even by second dimension analysis it was virtually undetectable in control heart. These results point to tissue-specific pathways for the post-transcriptional handling of mitochondrial mRNAs and suggest that the biochemical defects in LSFC reflect the differential ability of tissues to adapt to the mutation.
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PMID:Tissue-specific responses to the LRPPRC founder mutation in French Canadian Leigh Syndrome. 2521 34

DAZAP1 is an evolutionarily conserved RNA-binding protein expressed in many tissues in mice and humans. DAZAP1-knockout mice carrying a partial loss-of-function (hypomorphic) allele exhibited severe deficiencies in spermatogenesis and cell growth, indicating that DAZAP1 plays a pivotal role in the development of germ and somatic cells. We have identified cox6c mRNA, which encodes a subunit of complex IV of the mitochondrial respiratory chain, as a target transcript regulated by DAZAP1. We found that DAZAP1 bound to cox6c mRNA derived from either the genomic DNA or a genome-type expression vector in cells, but not to cox6c mRNA derived from an intronless expression vector. Interestingly, the presence of the last intron was sufficient for DAZAP1 binding to the mRNA, suggesting specific intron dependent DAZAP1 loading onto cox6c mRNA. Overexpression of DAZAP1 resulted in the accumulation of cox6c pre-mRNA for all introns, implying that DAZAP1 reduces pre-mRNA splicing efficiency. In addition, the reduction of mature cox6c mRNA levels led to decreases in the COX6C protein levels. Both DAZAP1 knockdown and COX6C overexpression retarded cell growth. The lines of evidence presented here reveal that DAZAP1 is a negative regulator of pre-mRNA splicing and may control energy production in mitochondria by regulating COX6C expression. The DAZAP1 functions described in this study may also account for the phenotypes observed in the DAZAP1 hypomorphic mice.
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PMID:Specific intron-dependent loading of DAZAP1 onto the cox6c transcript suppresses pre-mRNA splicing efficacy and induces cell growth retardation. 2950 34