# Mitochondrial transport of catalytic RNAs and targeting of the organellar transcriptome in human cells

## TL;DR

This paper introduces a new method to eliminate harmful mitochondrial RNAs in human cells using virus-derived RNA structures, which could help treat mitochondrial diseases.

## Contribution

A novel strategy using tRNA-like structures from viruses to deliver ribozymes into mitochondria for RNA knockdown.

## Key findings

- Targeted mitochondrial ATP6 mRNA was specifically knocked down using tRNA-like structures from Brome mosaic virus or Tobacco mosaic virus.
- Knockdown of ATP6 mRNA led to reduced ATP6 protein levels and impaired oxidative phosphorylation.
- The approach offers a powerful tool to study and potentially treat mitochondrial genetic disorders.

## Abstract

Mutations in the small genome present in mitochondria often result in severe pathologies. Different genetic strategies have been explored, aiming to rescue such mutations. A number of these strategies were based on the capacity of human mitochondria to import RNAs from the cytosol and designed to repress the replication of the mutated genomes or to provide the organelles with wild-type versions of mutant transcripts. However, the mutant RNAs present in mitochondria turned out to be an obstacle to therapy and little attention has been devoted so far to their elimination. Here, we present the development of a strategy to knockdown mitochondrial RNAs in human cells using the transfer RNA-like structure of Brome mosaic virus or Tobacco mosaic virus as a shuttle to drive trans-cleaving ribozymes into the organelles in human cell lines. We obtained a specific knockdown of the targeted mitochondrial ATP6 mRNA, followed by a deep drop in ATP6 protein and a functional impairment of the oxidative phosphorylation chain. Our strategy provides a powerful approach to eliminate mutant organellar transcripts and to analyse the control and communication of the human organellar genetic system.