Discussion in 'Other Health News and Research' started by merylg, Aug 7, 2017.
Here's the (v.complex) abstract of the original paper:
Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome
The synthesis of all 13 mitochondrial DNA (mtDNA)-encoded protein subunits of the human oxidative phosphorylation (OXPHOS) system is carried out by mitochondrial ribosomes (mitoribosomes). Defects in the stability of mitoribosomal proteins or mitoribosome assembly impair mitochondrial protein translation, causing combined OXPHOS enzyme deficiency and clinical disease.
Here we report four autosomal-recessive pathogenic mutations in the gene encoding the small mitoribosomal subunit protein, MRPS34, in six subjects from four unrelated families with Leigh syndrome and combined OXPHOS defects. Whole-exome sequencing was used to independently identify all variants. Two splice-site mutations were identified, including homozygous c.321+1G>T in a subject of Italian ancestry and homozygous c.322−10G>A in affected sibling pairs from two unrelated families of Puerto Rican descent.
In addition, compound heterozygous MRPS34 mutations were identified in a proband of French ancestry; a missense (c.37G>A [p.Glu13Lys]) and a nonsense (c.94C>T [p.Gln32∗]) variant. We demonstrated that these mutations reduce MRPS34 protein levels and the synthesis of OXPHOS subunits encoded by mtDNA. Examination of the mitoribosome profile and quantitative proteomics showed that the mitochondrial translation defect was caused by destabilization of the small mitoribosomal subunit and impaired monosome assembly.
Lentiviral-mediated expression of wild-type MRPS34 rescued the defect in mitochondrial translation observed in skin fibroblasts from affected subjects, confirming the pathogenicity of MRPS34 mutations. Our data establish that MRPS34 is required for normal function of the mitoribosome in humans and furthermore demonstrate the power of quantitative proteomic analysis to identify signatures of defects in specific cellular pathways in fibroblasts from subjects with inherited disease.
This (taken from the much more readable press release) makes the mitoribosome proteomics look very promising for discovering genetic (and maybe epigenetic) problems at the mitochondrial level.
"Published last week in the American Journal of Human Genetics, research co-led by Monash BDI researcher Dr David Stroud and MCRI PhD student Nicole Lake found a new cause of mitochondrial disease, which affects the ability of the mitochondria to operate as the body’s power plant, converting food into energy.
Ms Lake said the research identified mutations in a gene called MRPS34, in six patients with the most common form of childhood mitochondrial disease, Leigh Syndrome, from Australia, France and the USA.
“A key approach was using quantitative proteomics. This process involves sampling all the proteins in a cell at once to identify any problems with the cellular machinery,” said Ms Lake.
“Using this technique, you get a snapshot of what’s happening in cells.”
The MRPS34 gene is one of 80 components of the mitochondrial protein synthesis machinery, known as the ‘mitoribosome’.
Co-lead author, Dr David Stroud, carried out the quantitative proteomics technique, examining cellular proteins in the patient’s cultured skin cells, versus healthy skin cells at the Monash BDI.
“This showed one half of the mitoribosome fell apart, meaning cells could not make the key proteins encoded by mitochondrial DNA”, said Dr Stroud.
“At the same time we could also measure the resulting defects in two of the five major components of the power plants that fuel the body’s energy. This is an amazing level of detail for a single diagnostic technique,” he said.
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