Terminating human mitochondrial protein synthesis: A shift in our thinking

Lightowlers, Robert N.; Chrzanowska-Lightowlers, Zofia M.A.

doi:10.4161/rna.7.3.12023

Cited by 13 publications

(9 citation statements)

References 29 publications

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“…Subsequent database searches revealed the presence of three additional open reading frames with homology to RF1 (mtRF1a, C12orf65 and ICT1), all of which are localized to mitochondria. All of these factors have the classical GGQ motif that promotes termination by triggering hydrolysis of the peptidyl-tRNA bond [119]. However, mtRF1 has a variant on the PXT tripeptide motif expected to function in stop codon recognition while mtRF1a has the expected sequence [123,124].…”

Section: Polypeptide Chain Termination and Ribosome Recycling In Mmentioning

confidence: 99%

Mechanism of protein biosynthesis in mammalian mitochondria

Christian

Spremulli

2012

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

180

143

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Protein synthesis in mammalian mitochondria produces 13 proteins that are essential subunits of the oxidative phosphorylation complexes. This review provides a detailed outline of each phase of mitochondrial translation including initiation, elongation, termination, and ribosome recycling. The roles of essential proteins involved in each phase are described. All of the products of mitochondrial protein synthesis in mammals are inserted into the inner membrane. Several proteins that may help bind ribosomes to the membrane during translation are described, although much remains to be learned about this process. Mutations in mitochondrial or nuclear genes encoding components of the translation system often lead to severe deficiencies in oxidative phosphorylation, and a summary of these mutations is provided.

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Section: Polypeptide Chain Termination and Ribosome Recycling In Mmentioning

confidence: 99%

Mechanism of protein biosynthesis in mammalian mitochondria

Christian

Spremulli

2012

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

180

143

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“…It was shown that in humans a single mitochondrial release factor, mtRF1a, is sufficient to release all nascent mitochondrial gene products from the mitoribosome. 1 Nevertheless, the only member of the human mitochondrial release factor family implicated in human disease is c12orf65. 2,3 We report on seven new patients from two different families with confirmed novel C12orf65 mutations and further expand and delineate the clinical spectrum of C12orf65 defects.…”

Section: Introductionmentioning

confidence: 99%

Delineation of C12orf65-related phenotypes: a genotype–phenotype relationship

et al. 2014

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C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families. In four family members affected with childhood-onset optic atrophy accompanied by slowly progressive peripheral neuropathy and spastic paraparesis, we identified a homozygous frame shift mutation c.413_417 delAACAA, which predicts a truncated protein lacking the C-terminal portion. In the second family, we studied three affected individuals who presented with early onset optic atrophy, peripheral neuropathy, and spastic gait in addition to moderate intellectual disability. Muscle biopsy in two of the patients revealed decreased activities of the mitochondrial respiratory chain complexes I and IV. In these patients, we identified a homozygous splice mutation, g.21043 T4A (c.282 þ 2 T4A) which leads to skipping of exon 2. Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. In addition, a clear genotypephenotype correlation is anticipated in which deleterious mutations which disrupt the GGQ-containing domain in the first coding exon are expected to result in a more severe phenotype, whereas down-stream C-terminal mutations may result in a more favorable phenotype, typically lacking cognitive impairment.

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“…A mitochondrial ribosome has three transfer RNA (tRNA)-binding sites of A (aminoacyl), P (peptidyl) and E (exit) sites which bind to their respective tRNAs on messenger RNAs 5–7. When a mitochondrial stop codon (UAA or UAG) is recognised at the A site of the ribosome, the RFs interact with the peptidyl-transeferase centre of the large ribosomal subunit via its GGQ motif 2 8. This conformation triggers the peptidyl-tRNA hydrolysis, which catalyses the hydrolysis of the ester bond between the nascent polypeptide and peptidyl-tRNA 1 2.…”

Section: Introductionmentioning

confidence: 99%