Mitochondrial performance enhanced by local protein production

In a groundbreaking study published today in the prestigious journal Cell, MIT professor Jonathan Weissman and postdoc Jingchuan Luo have developed a new tool, LOCL-TL, to study localized protein translation in detail, particularly at mitochondria.

The study identifies two distinct groups of proteins that are locally translated at mitochondria. The first group consists of long proteins (> 400 amino acids) of bacterial origin, present in the ancestor of mitochondria. These proteins begin production anywhere in the cell and get transported to mitochondria after approximately the first 250 amino acids are made.

The production and import of these long proteins tie up the channel for a long time, limiting the import of other proteins. Weissman's lab previously developed a method called proximity-specific ribosome profiling to study localized translation. They adapted this method to respond to blue light instead of biotin, creating the new tool, LOV-BirA, which is fused to the mitochondrion's outer membrane. When activated by blue light, LOV-BirA captures only ribosomes working at mitochondria.

The second group consists of short proteins (< 200 amino acids) that are more recently evolved and have a different mechanism for their localized translation. The researchers identify the RNA binding protein AKAP1 as involved in the recruitment of short proteins to mitochondria. Eliminating AKAP1 leads to the indiscriminate translation of these proteins throughout the cell, causing the loss of various mitochondrial proteins, including those involved in oxidative phosphorylation.

The mechanism for localized translation of short proteins at mitochondria is different from that in yeast. It occurs at the RNA level, involving specific sequences within regulatory sections of each RNA molecule. Localized translation may help cells manage the interplay between mitochondrial and nuclear protein production.

Future research will focus on how localized translation affects mitochondrial function and dysfunction in disease, as well as its role in other cellular processes such as embryonic development, neural plasticity, and disease. The challenge was to modify this method to capture only ribosomes at work near mitochondria. The researchers then used a method to extract the sections of RNA inside of the captured ribosomes, which reveals how far along in the process of making a protein the ribosome is when captured.

Mitochondria were once bacteria that lived within cells and have lost their autonomy over time. Understanding the mechanisms of localized protein translation at mitochondria could provide valuable insights into the evolution of these organelles and their essential roles in cellular function.