Researchers Find Key Quality Control Mechanism in Mitochondrial Protein Production

The body’s ability to ensure error-free activity of transfer RNA (tRNA), which is essential to the production of protein, is important in the accurate operation of the mitochondria. Researchers have now found a quality-control mechanism that double-checks the correct protein sequence and may help prevent disease.

The study, “Editing activity for eliminating mischarged tRNAs is essential in mammalian mitochondria,” was published in the journal Nucleic Acids Research.

The function of the mitochondria, which provides energy to cells, is important in maintaining cellular stability. Most of the cell’s proteins are produced in the cytoplasm, which is the fluid that fills the cells. However, in order to carry out some of the important functions, the mitochondria produces its own proteins.

The process of producing a protein molecule requires two steps. First, DNA is converted to a molecule called mRNA in a process called transcription. Then, mRNA is converted into a protein molecule in a process called translation. tRNAs are major components of the machinery that carries out translation. Protein molecules are essentially a chain of amino acids that are joined together by tRNAs.

Mammalian mitochondria import tRNAs to produce proteins that are vital for the proper function of mitochondria. There are several mechanisms that control mitochondrial protein integrity.

Dr. Henna Tyynismaa’s group at the University of Helsinki studies mitochondrial enzymes called aminoacyl-tRNA synthetases (ARSs) that attach amino acids to the tRNA. However, these ARSs can sometimes attach the wrong amino acid to the wrong tRNA. This could lead to the wrong amino acid sequence in the resulting protein, unless the enzyme has a mechanism to correct its mistakes.

Tyynismaa’s lab showed that the mitochondrial enzyme alanyl-tRNA synthetase (mtAlaRS) has a highly conserved domain in its structure that is responsible for editing the improper addition of the wrong amino acid to a tRNA. The presence of a highly conserved domain indicates that this part of the protein has remained essentially unchanged throughout evolution and that is both unique and essential for the function of the protein.

“We found that the error-correction mechanism of this mitochondrial enzyme is vital for the cell: even a slight decrease in the correction mechanism had an adverse effect on the function of the cell. The significance of this mechanism for the mitochondria was previously unknown,” Tyynismaa said in a press release.

Her lab has also created an editing-deficient mtAlaRS mouse model to determine the effect of mitochondrial faulty protein production in an animal model. These mice either had a mild or a severe mtAlaRS editing mutation.

Interestingly, these mutations led to early embryonic death in mice, which means mice with this mutation did not survive to birth. This demonstrates the importance of the editing function of an AlaRS in mammalian mitochondria.

It is known that abnormal mitochondrial protein production can lead to many different hereditary diseases. This enzyme, AlaRS, is particularly known to have mutations which can cause severe neonatal heart disease or a neurological disease with onset in early adulthood.

“We do not currently know whether these diseases are the result of the weakened ability of the enzyme to attach the correct amino acids to the transfer RNA or problems in its error-correction mechanism. A better understanding of the enzyme’s fundamental mechanisms may help us determine the impact of the faulty genes in the future,” Tyynismaa said.