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A small, multi-functional molecule can tag mutant genetic sequences inside mitochondria for elimination

This new compound can discover and assist take away mutant mitochondria DNA from cells. Credit: Mindy Takamiya/Kyoto University iCeMS

Mutant DNA sequences inside mobile mitochondria could be eradicated utilizing a bespoke chemical compound. The method, developed by scientists at Kyoto University’s Institute for Integrated Cell-Material Science (iCeMS) in Japan, might result in higher therapies for mitochondrial illnesses. The researchers printed their findings within the journal Cell Chemical Biology.

Mitochondria carry out many cell features, together with energy production, biomolecule synthesis and calcium homeostasis. Mitochondria have their very own DNA, completely different from the DNA discovered contained in the cell’s nucleus. Mutations on this mitochondrial DNA can result in illnesses, inflicting blindness, muscle weak spot and even demise.

In some mitochondrial illnesses, mutated DNA and regular DNA co-exist. “This state is called heteroplasmy,” explains Kyoto University’s Takuya Hidaka, the primary creator of the examine. “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.”

Current approaches for such mitochondrial diseases are problematic, explains iCeMS bioengineer Ganesh Namasivayam Pandian, who led the examine. Some contain injecting genetic material into cells, which might result in undesirable alterations. In others, antioxidant medicine are administered to cut back the impacts of the mutant DNA, with out addressing the core mutation.

Pandian labored with iCeMS chemical biologist Hiroshi Sugiyama, Takuya Hidaka and colleagues to develop a chemical-based method that overcomes these points.

They designed a compound fabricated from a mitochondria-penetrating peptide (MPP) certain to a polymer, known as a pyrrole-imidazole polyamide (PIP), which could be modified to focus on a selected DNA sequence. These had been then connected to an present anti-cancer drug, known as chlorambucil.

The MPP takes the compound into the mitochondria, the place the PIP binds to its goal DNA sequence. This permits the chlorambucil to wreck the focused DNA for elimination. Analyses confirmed the method decreased the quantity of mutant mitochondrial DNA in lab cultures of human cells. Further analysis utilizing disease fashions is required to find out the method’s effectiveness inside a residing organism.

By adapting the chemical make-up of the PIP, the therapeutic compounds could be programmed to connect to completely different DNA sequences, and so goal a spread of mitochondrial genetic illnesses.

“Our proof-of-concept study can be extended to mitochondrial mutations that cause diseases like Leber’s hereditary optic neuropathy, an inherited form of vision loss that currently has no proven treatment,” says Pandian.

Accessing DNA in the cell’s powerhouse to treat disease

More info:
Takuya Hidaka et al, Targeted elimination of mutated mitochondrial DNA by a multi-functional conjugate able to sequence-specific adenine alkylation, Cell Chemical Biology (2021). DOI: 10.1016/j.chembiol.2021.08.003

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Kyoto University

A small, multi-functional molecule can tag mutant genetic sequences inside mitochondria for elimination (2021, August 27)
retrieved 27 August 2021
from https://phys.org/news/2021-08-small-multi-functional-molecule-tag-mutant.html

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