New Molecule Promises To Shield Mitochondrial DNA Against Disease

Scientists have developed a new molecule called mTAP that protects the DNA of mitochondria, the "power plants" of cells, from damage. This molecule specifically targets weak points in mitochondrial DNA, preventing their destruction and helping maintain their function. This could pave the way for new treatments for genetic diseases linked to the loss of cellular energy.

Mitochondria are structures within cells that function as veritable "power plants," transforming nutrients into usable energy for cellular activities. But they do much more than that: they also participate in controlling metabolism, communication between cell parts, and the overall balance of the cellular environment.

They arose about 2 billion years ago from the union between a primitive cell and a bacterium, in a process called endosymbiosis. Unlike other parts of the cell, mitochondria have their own DNA, called mitochondrial DNA (or mtDNA).

This DNA is much smaller than that of the cell nucleus, but it is essential: it carries instructions for making important proteins that aid in energy production. Furthermore, mtDNA can act as a "molecular alarm," alerting the body to cellular damage and activating the immune system.

Like all DNA, mtDNA can be damaged, especially when the cell is under stress, such as during infection or exposure to toxins. One of the most common types of damage occurs when parts of DNA bases are removed, forming so-called abasic sites (or AP sites).

When this happens, the body needs to repair the problem quickly to prevent further damage. One of the main repair systems is called BER (base excision repair), which involves enzymes that identify and replace these damaged parts.

However, if mtDNA is severely damaged and cannot be repaired, it can be destroyed by the cell itself, affecting energy production. This can lead to serious genetic diseases known as mtDNA depletion syndromes, in which there is a massive loss of mitochondrial DNA in the affected tissues. Unfortunately, to date, there are no effective medications to prevent this loss under stress.

To try to solve this problem, researchers created a molecule called mTAP, a chemical probe specifically designed to enter mitochondria and bind to the AP sites of mtDNA.

The idea is that by binding to these damaged sites, mTAP prevents them from being cut or removed, which could prevent mitochondrial DNA degradation.

The water-soluble probe mTAP, which targets mitochondria, reacts exclusively with mitochondrial abasic sites, allowing the manipulation of mitochondrial DNA levels under genotoxic stress.

In experiments, the scientists showed that mTAP acts only on mitochondria, without affecting nuclear DNA, which is crucial for avoiding side effects.

They also demonstrated that, when using mTAP, cells were able to maintain more stable levels of mtDNA and its genetic messages (transcripts), even under conditions that would normally cause their loss.

Furthermore, mTAP does not interfere with mtDNA replication (copying) or cause new damage, making it a promising tool for protecting mitochondrial DNA without causing additional damage. This discovery may pave the way for new therapeutic strategies for mitochondrial diseases and other conditions related to cellular stress.

Scientists have developed a technique to precisely measure how much of the new protective molecule (called mTAP) binds to mitochondrial DNA. A) First, they carefully separated mitochondrial DNA (mtDNA) from the cell's nuclear DNA (nDNA). B-C) Then, both types of DNA were broken into smaller pieces and analyzed with highly sensitive instruments capable of detecting even minute amounts of the DNA-bound substance. E) The results showed that mTAP binds almost exclusively to mitochondrial DNA, not to nuclear DNA, which is important because it indicates that the molecule acts specifically and safely. This discovery reinforces mTAP's potential as a precise tool for protecting mitochondrial DNA without interfering with other parts of the cell.

READ MORE:

Mitochondria-Targeting Abasic Site-Reactive Probe (mTAP) Enables the Manipulation of Mitochondrial DNA Levels

Dr. Anal Jana, Yu-Hsuan Chen, and Dr. Linlin Zhao

Angewandte Chemie International Edition, 15 July 2025, e202502470

https://doi.org/10.1002/anie.202502470

Abstract: 

Mitochondrial DNA (mtDNA) encodes essential genes for mitochondrial and cellular functions and acts as a cell signaling molecule in innate immune and inflammatory responses. Defects in mtDNA are implicated in a range of mitochondrial disorders and human diseases. Currently, no chemical strategy exists to prevent mtDNA loss under genotoxic stress. To address this, we developed a mitochondria-targeting probe (mTAP) that selectively reacts with key mtDNA repair intermediates–abasic (AP) sites. We confirmed that mTAP forms oxime conjugates exclusively with mitochondrial AP sites without conjugation with nuclear AP sites. Upon mTAP conjugation, DNA substrates containing AP sites were resistant to cleavage by AP endonuclease (APE1) and mitochondrial extracts. This conjugation significantly reduced the DNA-binding affinity of APE1 without affecting the DNA-binding activity of a mtDNA-packaging factor, mitochondrial transcription factor A (TFAM). Importantly, cellular experiments demonstrated that mTAP treatment alleviated the decrease in mtDNA and transcription product levels induced by mitochondrial AP site damage. Functional assays also demonstrated that mTAP treatment did not compromise mtDNA replication activity or increase the overall mtDNA damage level. These findings highlight the potential of mTAP as a valuable chemical tool to modulate mtDNA levels under genotoxic stress.