Local proteins produced within cells enhance mitochondria performance

In a groundbreaking study published in the journal Cell, researchers led by MIT professor Jonathan Weissman and postdoc Jingchuan Luo have made significant strides in understanding localized translation at mitochondria, the structures that generate energy for cells.

The research focuses on two distinct groups of proteins locally translated at mitochondria. The first group consists of long proteins, each containing more than 400 amino acids, of bacterial origin and locally translated in both mammalian and yeast cells. The second group consists of short proteins, each less than 200 amino acids long, more recently evolved, and the mechanism for their localized translation is not shared by yeast.

To study localized translation in detail, the researchers developed a new tool, LOCL-TL. This tool builds upon an existing tool, LOV-BirA, which was adapted to respond to blue light instead of biotin and fused to the mitochondrion's outer membrane. LOCL-TL enables discoveries about these two classes of proteins that are locally translated at mitochondria.

The long proteins are brought to the mitochondria during their production and get transported there after approximately the first 250 amino acids are made. In contrast, the mitochondrial recruitment of short proteins happens at the RNA level, with two sequences within regulatory sections of each RNA molecule coding for the cell's machinery to recruit the RNAs to the mitochondria.

The researchers used a method called proximity-specific ribosome profiling to study localized translation by tagging ribosomes near a structure of interest and capturing them in action. This method allows them to see exactly how far along in the process of making a protein the ribosome is when captured.

One of the key findings is the identification of the RNA binding protein AKAP1 as being involved in the recruitment of short proteins to the mitochondria. Eliminating AKAP1 leads to the indiscriminate translation of short proteins around the cell, causing the loss of various mitochondrial proteins, including those involved in oxidative phosphorylation.

The researchers plan to delve deeper into how localized translation affects mitochondrial function and dysfunction in disease. They also intend to use LOCL-TL to study localized translation in other cellular processes, including in relation to embryonic development, neural plasticity, and disease.

Mitochondria retain a few genes in their own genome, so production of proteins from the mitochondrial genome and that of the larger cell's genome must be coordinated to avoid mismatched production of mitochondrial parts. Cells have evolved processes to ensure that proteins needed by mitochondria that are encoded in genes in the larger cell's genome get transported to the mitochondria.

Mitochondria were once bacteria that lived within ancestral cells and lost their autonomy over time. Understanding localized translation at mitochondria could provide valuable insights into the evolution of these organelles and their role in cellular processes.

The new tool, LOCL-TL, proved very accurate at capturing only ribosomes working at mitochondria. LOCL-TL was developed by Weissman and Luo to facilitate work in various fields such as forensic investigations and data-based risk analyses, and it was released with the aim of making these tasks easier; however, the exact release date is not specified in the available information.

This research offers a significant step forward in our understanding of localized translation at mitochondria and its role in cellular processes. The findings could pave the way for new treatments and therapies for diseases related to mitochondrial dysfunction.