A team at Sun Yat-sen University maps translational fidelity and lifespan in yeast progeny, identifies the VPS70 locus via QTL analysis, and demonstrates that replacing the BY allele with the RM variant reduces translation errors and extends chronological lifespan by ~8.9%.
Key points
QTL mapping in long-lived BY×RM yeast segregants identifies overlapping locus on chrX containing VPS70.
Allelic replacement of BY VPS70 with RM variant reduces translation error rate by ~8% as measured by dual luciferase assays.
VPS70-RM extends yeast chronological lifespan by ~8.9%, and Concanamycin A abrogates both fidelity and longevity effects, confirming vacuole dependence.
Why it matters:
This work reveals translational fidelity as a heritable determinant of lifespan, highlighting vacuolar protein sorting as a potential target for longevity interventions.
Q&A
What is translational fidelity?
How does VPS70 affect protein quality control?
What is QTL mapping?
What does chronological lifespan measure in yeast?
Why use Concanamycin A in this study?
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Academy
Translational Fidelity: Ensuring Accurate Protein Synthesis
Translational fidelity refers to the accuracy with which the ribosome decodes mRNA codons into the correct amino acids, producing functional proteins. High fidelity is crucial to prevent protein misfolding, aggregation, and cellular stress, which are linked to aging and disease.
1. How Translation Works- The ribosome reads mRNA codons sequentially and pairs each codon with a specific transfer RNA (tRNA) carrying its matching amino acid.
- Peptide bonds form between amino acids, elongating the polypeptide chain until a stop codon is encountered.
2. Sources of Translational Errors- Misreading: Incorrect tRNA pairs with a codon, leading to the wrong amino acid insertion.
- Frameshifts: Ribosome slips by one nucleotide, altering downstream codon reading.
- Premature termination: Early stop codon recognition truncates the peptide.
3. Cellular Quality-Control Mechanisms- Proofreading by ribosomal factors: Elongation factors accelerate rejection of incorrect tRNAs.
- Proteasomal degradation: Misfolded proteins are tagged with ubiquitin and degraded by proteasomes.
- Vacuolar/lysosomal clearance: In yeast, misfolded proteins are delivered to vacuoles for breakdown.
4. Role of Vacuolar Protein SortingThe vacuole is the yeast equivalent of the lysosome and plays a key role in degrading damaged or aggregated proteins. Proteins such as VPS70 facilitate the recognition and trafficking of defective proteins into the vacuole, maintaining proteostasis.
5. Translational Fidelity and AgingAccumulated errors in protein synthesis can overwhelm quality-control systems, causing toxic aggregates, cellular dysfunction, and reduced lifespan. Enhancing fidelity may alleviate this burden and promote longevity.
6. Yeast as a Model OrganismBudding yeast (Saccharomyces cerevisiae) offers genetic tractability and well-characterized aging assays. Researchers measure chronological lifespan by tracking the survival of non-dividing cells over time, modeling aspects of aging in post-mitotic cells.
7. Implications for Human AgingWhile humans have complex tissues and additional regulatory layers, the fundamental mechanisms of translation and proteostasis are conserved. Insights from yeast may guide therapies that target protein quality control to slow age-related decline.
