Sequence-Selective mtDNa Alkylators Developed

A new approach developed by scientists at Kyoto University’s Institute for Integrated Cell-Material Science in Japan allows for mutant DNA sequences inside cellular mitochondria to be eliminated using a bespoke chemical compound. The researchers published their findings in Cell Chemical Biology.

In some mitochondrial diseases, mutated DNA and normal DNA co-exist. “This state is called heteroplasmy,” explains Takuya Hidaka, the first author of the study. “Mitochondrial function can be maintained by normal mitochondrial DNA when the heteroplasmy level is low. But it is impaired when mutated DNA exceeds a critical threshold. To cure mitochondrial diseases, we need to be able to remove mutant mitochondrial DNA from cells.”

The team designed a compound made of a mitochondria-penetrating peptide (MPP) bound to a polymer, called a pyrrole-imidazole polyamide (PIP), which can be modified to target a specific DNA sequence. These were then attached to an existing anti-cancer drug, called chlorambucil.

The MPP takes the compound into the mitochondria, where the PIP binds to its target DNA sequence. This allows the chlorambucil to damage the targeted DNA for elimination. Analyses showed the technique reduced the amount of mutant mitochondrial DNA in lab cultures of human cells. Further research using disease models is needed to determine the approach’s effectiveness inside a living organism. By adapting the chemical make-up of the PIP, the therapeutic compounds can be programmed to attach to different DNA sequences, and so target a range of mitochondrial genetic diseases.