Mitochondrial proteostatic mechanisms Mitochondrial proteins are essential players in maintaining mitochondrial health. These organelles are home to the processes that generate ATP (adenosine triphosphate), the molecular fuel that energizes a myriad of cellular functions. For the past 30 years, scientists have followed the dogma that these proteins are imported only after their production is finished. Shu-ou Shan and her colleagues discovered this in a really cool way. From this they concluded that the import of up to 20% of mitochondrial proteins occurs cotranslationally, meaning they’re imported into the mitochondria while they’re still being made.
This new work, published in the journal Cell, reveals the intricate and remarkable mechanisms that control mitochondrial protein import. During translation, a process inescapably linked to the evolution of life on Earth, proteins are synthesized on ribosomes. Some mitochondrial proteins are able to initiate their import process even while still being unfolded. Unraveling this mystery goes against decades of dogma in the field of biochemistry and presents exciting new possibilities for studying mitochondrial function.
New Insights into Protein Synthesis
Mitochondrial proteins are key players in maintaining cellular energy homeostasis. In the past, scientists thought that proteins needed to be completely synthesized in the cytosol to begin with. Afterwards, they might be freshly imported into the mitochondria. This model was a gross simplification that painted a static picture of the protein synthesis process. Roughly during this process, the ribosome ceaselessly provides amino acids to a protracted chain according to the genetic code.
Shu-ou Shan, the Altair Professor of Chemistry at Caltech and co-corresponding author, described the significance of these results. She cautioned, “You’re going to be in this huge, complex protein structure if you let them complete translation out in the cytosol. Otherwise, they’ll find themselves ensnared in permanent boondoggles. Second, you won’t merely stop your imports; you’ll jam every channel.
Shan and her team did an extensive research, which ultimately fed them to a surprising find. Lastly, they tangentially identified a subset of mitochondrial proteins that could be imported cotranslationally. Lead author Zikun Zhu explained the significance of this discovery: “Once we identified these mitochondrial proteins that are cotranslationally imported, we asked, ‘What is special about this subset of proteins?’”
The Mechanism of Cotranslational Import
This was the first time that detailed molecular mechanisms were identified to trigger efficient mitochondrial protein import. This signal comes from the ribosome, generated during the process of translation. We use the signal of the first large protein domain or foldable structural unit in the protein sequence. Zhu conducted experiments demonstrating that the import system waits for this critical signal before proceeding with cotranslational import.
It’s as if your boarding pass is in a suitcase,” Zhu continued. Holding this targeting sequence is like having a boarding pass, but in order to even get to that boarding pass, you need the code to unlock that suitcase. For this case, the big domain is that code. This analogy helps to demonstrate why careful folding and preparation of the protein is so important before import can begin.
Shan took a deep dive into the nitty gritty, including the transparency of the process. He continued, “That becomes a much more complex process than just collapsing by way of contacts between adjacent residues.” Just-in-time import is key for all kinds of cellular functions. This highlights the need to parse through what’s actually going on under the hood mechanistically.
Collaborative Efforts and Future Implications
Shan, Zhu, and their group undertook a massive study. They benefited greatly from the expert input of Saurav Mallik, Weizmann Institute of Science, Israel and Emmanuel D. Levy, University of Geneva, Switzerland. Collectively, they have brought unprecedented understanding into cotranslational mitochondrial protein import that will likely redefine future work in biochemistry.
These findings overhaul current paradigms. Their work lays the groundwork for further investigation into how mitochondrial function plays a role in cellular health. Knowing how proteins are directed to mitochondria as they are being made will spur progress in a variety of biotechnological applications. Such understanding can further result in innovative therapeutic approaches for different diseases associated with mitochondrial malfunction.