Research Highlight

Novel way to correct a genetic disorder affecting the eyes

doi:10.1038/nindia.2021.95 Published online 6 July 2021

Researchers in Delhi have identified a novel molecular mechanism that leads to autosomal dominant progressive external ophthalmoplegia (adPEO), a disorder that gradually weakens the muscles in the eyes, neck, arms and legs1. The team, from the National Institute of Immunology (NII), has also found a way that they say can alter this mechanism and alleviate this disorder.   

This disorder stems from mutations in a gene that encodes the enzyme polymerase gamma A (poly gamma A). This enzyme helps replicate and repair the DNA of mitochondria.

After its production in a cell’s nucleus, poly gamma A enters the mitochondria. In experiments with specific cells, the researchers found that ubiquitylation, a process that adds an ubiquitin protein to another protein, regulates the entry of the enzyme into mitochondria.  

The NII team, led by Sagar Sengupta, discovered that a protein called MITOL, located on the outer membrane of mitochondria, aids the ubiquitylation that prevents the entry of highly ubiquitylated defective poly gamma A into mitochondria. This, in turn, disrupts the DNA replication and repair in mitochondria.

The researchers found that in 50 per cent of adPEO patients, the defective enzyme cannot enter the mitochondria and perform its functions.

Next, they showed that removing MITOL or genetically modifying the ubiquitylation paved the entry of the defective enzyme into mitochondria, restoring its functions near to the levels of normal enzymes.  

In the future, the researchers want to test whether such modification of the defective mitochondrial enzyme could actually be carried out in humans using mitochondrial genome-editing techniques. 



1. Hussain, M. et al.  MITOL-dependent ubiquitylation negatively regulates the entry of PolγA into mitochondria. PLoS. Biol. 19 (3):e3001139 (2021) DOI: 10.1073/journal.pbio.3001139