Mitochondrial translational defect extends lifespan in C. elegans by activating UPR^mt

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Aminoacyl-tRNA synthetases (aaRSs) are essential for protein synthesis.
• Eukaryotes typically use multiple genes for cytoplasmic and mitochondrial threonyl-tRNA synthetases (ThrRSs).
• The genetic basis and function of ThrRSs in C. elegans remain incompletely understood.

Purpose of the Study:

• To investigate the mechanism of ThrRS gene expression in C. elegans.
• To elucidate the physiological roles of mitochondrial ThrRS in C. elegans.
• To explore the link between mitochondrial function and conserved stress responses.

Main Methods:

• Genetic analysis of the tars-1 gene in C. elegans.
• Assessment of mitochondrial tRNA charging and translation efficiency.
• Measurement of mitochondrial respiration and enzyme activities.
• Induction and analysis of the mitochondrial unfolded protein response (UPR^mt).

Main Results:

• C. elegans utilizes a single tars-1 gene to generate both cytoplasmic and mitochondrial ThrRSs via translational reinitiation.
• Mitochondrial tars-1 deficiency impairs mitochondrial translation, leading to developmental delays, reduced motor function, and extended lifespan.
• Mitochondrial dysfunction, including decreased oxygen consumption and Complex I activity, activates the UPR^mt, contributing to longevity.
• Deficiency in other mitochondrial aaRSs also activates the UPR^mt, indicating a conserved response.

Conclusions:

• A single gene encodes dual-localized ThrRSs in C. elegans through translational reinitiation.
• Mitochondrial ThrRS is crucial for mitochondrial function, development, and lifespan in C. elegans.
• Mitochondrial translation deficiency is linked to the conserved UPR^mt pathway, impacting longevity.