Caltech researchers upset a model for importing mitochondriat protein several decades

Researchers have shown that many mitochondrial proteins are part of the ordeal during synthesis, guided by folding models and structural signals. This discovery revises decades of biochemical models.

Mitochondria are the most commonly known organelles under the name of “cell powerhouses” because they generate ATP (adenosine triphosphate), the main source of energy for most cellular activities. They created more than a billion years ago when an ancestral archaeal cell formed a symbiotic partnership with a bacteria.

During evolutionary time, mitochondria has become essential for metabolism and energy production, transferring most of their genetic equipment to the host cell. Consequently, they now depend on the host to produce the majority of their proteins, which are synthesized by ribosomes outside the organel and must be transported with precision in the mitochondria.

Caltech researchers have now revealed new perspectives on how these proteins are moved from ribosomes in cytosol, liquid surrounding the nucleus, in mitochondria. Unexpectedly, they found that the path is strongly influenced by protein folding mechanisms.

“It turns out that the location of mitochondria proteins implies a complex multilayer route which is wired around the biophysical principles of protein folding,” explains Shu-Ou Shan, professor of Altair chemistry in Caltech.

Question the traditional model

For many years, the dominant biochemistry vision was that mitochondrial proteins are only imported after translation – the process in which ribosomes build proteins by linking amino acids Together according to the genetic code – is completely finished. In a new study published in CellShu-ou Shan and his team challenge this model, indicating that up to 20% of mitochondrial proteins are imported cotranslation. In other words, these proteins are starting to enter the mitochondria while they are still assembled on ribosomes.

“Once we have identified these mitochondrial proteins which are imported cotranslationally, we asked:” What is the particularity of this protein subset? “” Said Zikun Zhu (Phd ’24), the former student graduated from Shan and the main author of the newspaper.

Proteins difficult to fold and import timing

The researchers discovered that the determining line of these proteins is their size and their structural complexity. Many of them are topologically complex, containing residues – amino acids in the chain – which can be distant in sequence but must come together to make the correct three -dimensional fold. “It becomes a much more difficult process than simply folding the interactions between neighboring residues,” notes Shan.

Consequently, the cotranslational import system in mitochondria hierartis these proteins really difficult to fold. This is logical if you consider that large structures must possibly go through narrow channels on the mitochondrial membrane during import. “There will be a problem if you let these large very complex proteins complete the translation in cytosol,” says Shan. “They will remain stuck in irreversible structures, then you will not only block importation, you will get all the channels.”

Molecular signals and targeting sequences

The team found that almost all of these proteins carry a mitochondrial targeting sequence, which is a signal that directs proteins to the mitochondria. However, surprisingly, this is not enough alone to indicate that this subset of protein is delivered during the translation. Zhu conducted experiences that have shown that the system is expecting a second molecular signal to move a protein early to mitochondria. This signal is in the form of the first large protein area, or foldable structural unit in the sequence, which emerges from the ribosome.

“It’s as if your boarding pass is locked in a suitcase,” explains Zhu. “The targeting sequence is the boarding card, but to access it, you need the code to open the suitcase. In this case, the large area is this code.”

Scientists have even been able to transplant examples of protein are also large towards other mitochondrial proteins which are normally imported after translation and have shown that the domains served as transferable signals capable of realloring proteins to import during translation.

“The cotranslational targeting of mitochondria turns out to be completely different from the targeting of other organelles,” explains Zhu. “In the future, it will be exciting to discover more mechanistic details and, in the end, to manipulate the time of importing mitochondrial proteins.

Reference: “Principles of importation of cotransulation mitochondrial proteins” by Zikun Zhu, Saurav Mallik, Taylor A. Stevens, Rimming Huang, Emmanuel D. Levy and Shu-U Shan, August 11, 2025, Cell.
DOI: 10.1016 / J.Cell.2025.07.021

This work was supported by the National Health Institutes Grant R35 GM136321 in S.-OS and the Howard Hughes Medical Institute through a Freeman Hrabowski Scholar subsidy in Rebecca Voorhees. EDL recognizes the support of the European Research Council (ERC) within the framework of the Research and Innovation Program Horizon 2020 of the European Union (grant agreement n ° 819318), by the organization of the program of human boundaries (ref. RGP0016 / 2022), and by the foundation of Israeli sciences (subsidy n ° 1452/18).

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