How mitochondria keep protein production moving
Researchers at Karolinska Institutet have discovered how a protein called TACO1 helps mitochondria produce proteins when the process encounters difficult sequences. The study, published in Nature Communications, provides new insights into a mechanism that is disrupted in some mitochondrial diseases.
Mitochondria supply cells with energy and produce a small but essential set of proteins needed for this process. The proteins are made by mitochondrial ribosomes, known as mitoribosomes.
During protein production, however, some sequences can cause the mitoribosome to slow down or stall. This is particularly true for sequences containing several copies of the amino acid proline. TACO1 is known to help the mitoribosome continue through such sequences, but exactly how it does this has remained unclear.
A closer look at how TACO1 works
Using cryo-electron microscopy, or cryo-EM, the researchers captured human TACO1 interacting with a mitoribosome while it was producing a protein. They found that TACO1 works differently from related factors found in bacteria and elsewhere in human cells.
TACO1 binds close to the ribosome’s A site, where new amino acids are brought in, and interacts directly with the incoming transfer RNA, or tRNA.
“TACO1 reveals a distinct solution to a challenge faced by all ribosomes: keeping protein synthesis moving through difficult sequences,” says Joanna Rorbach, professor at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet and lead corresponding author of the study.
The researchers combined cryo-EM with AlphaFold analysis, computational modelling and molecular dynamics simulations. Their results suggest that TACO1 can undergo substantial movements that help stabilise the incoming tRNA during challenging steps in protein production.
“Combining cryo-EM with AlphaFold analysis and molecular dynamics simulations allowed us to explore how TACO1’s flexibility may help position the incoming tRNA,” says Vivek Singh, postdoctoral researcher at Karolinska Institutet and first author.
“These findings help connect changes in TACO1 to defects in mitochondrial protein synthesis, offering a clearer molecular basis for understanding associated diseases,” says Anas Khawaja, research specialist at Karolinska Institutet and co-corresponding author.
The researchers also found structural similarities between TACO1 and its bacterial relative YebC2, pointing to an evolutionarily conserved mechanism. Mutations in TACO1 are associated with cytochrome c oxidase deficiency and late-onset Leigh syndrome. The findings provide a molecular explanation for how changes in TACO1 may interfere with mitochondrial protein synthesis.
Publication
Structural basis of TACO1-mediated efficient mitochondrial translation.
Wang S, Brischigliaro M, Zhang Y, Wu C, Zheng W, Barrientos A, Xiong Y
Nat Commun 2026 Feb;17(1):