New way to target mitochondrial diseases

The market for mitochondrial diseases is currently small at just over €23m. However, it is growing by 28.5% annually until 2030 as the disease mechanisms of at least 1.6 million patients worldwide are increasingly being decoded. German scientists have now developed a method  to silence specific mitochondria-encoded mRNAs in living cells, opening the avenue towards phenotypic screens.

Mitochondrial defects are linked to a wide range of diseases, including disorders affecting tissues with high energy demands like the brain, muscles, and heart. To better model these disorders, researchers need to be able to manipulate mitochondrial gene expression and evaluate how this impacts mitochondrial protein synthesis. To date, however, approaches that allow this process in a simple manner in cells are not available.

To fill this gap, Luis Cruz-Zaragoza et al. developed a way to target multiple mRNAs simultaneously in different cell types. Their approach involved using synthetic peptide-morpholino chimeras generated by click chemistry. They tested their technique in cells including human cardiomyocytes and mouse liver cells – finding it could block mitochondrial protein production consistently. Applying this technique also revealed how mitochondrial gene expression affects cellular homeostasis. “The availability of this chimera-based mitochondrial mRNA silencing strategy provides a valuable tool for researchers to study mitochondrial gene expression, protein biogenesis, and their integration into cellular physiology,” said Cruz-Zaragoza.

His approach allowed to perform a comprehensive temporal monitoring of cellular responses such as mitochondrial translation, its integration into cellular physiology. It provides a strategy to address mitochondrial gene expression in living cells that can be used to analyze mechanisms and pathophysiology of mitochondrial gene expression in a range of cellular model systems.