Ubiquitin-Mediated Mitophagy Regulates The Inheritance of Mitochondrial DNA Mutations

A recent study published in the journal Science has revealed a cellular mechanism for the transmission of genetic mutations and points to a potential treatment that could reduce the risk of infants developing severe and incurable mitochondrial diseases.

This study found that overactivation of the USP30 enzyme inhibits ubiquitin-labeled defective mitochondria, allowing mutated mitochondrial DNA to escape the "quality control system" and be inherited by offspring. Inhibiting USP30 using the compound CMPD39 creates a "clearance window" after fertilization, effectively eliminating mutated mitochondrial DNA. These findings provide new pharmacological insights for the prevention of mitochondrial diseases.

According to the results, the transmission of these mutations involves a process that both prevents the clearance of mutated mitochondria and increases their numbers in the cell. This explains how these mutations "escape" selection and may lead to disease in the future.

Mitochondria are the primary energy source for all cells and possess their own DNA. Shortly after fertilization, the embryo initiates a "quality control" system to eliminate "defective" mitochondria, a process called mitophagy. During this process, ubiquitin acts as a marker, guiding altered molecules toward destruction. Mitophagy maintains harmony between mitochondrial DNA and nuclear DNA, ensuring their compatibility. However, the mutation rate of mtDNA is approximately 15 times higher than that of the nuclear genome, posing a challenge to their symbiotic relationship.

The USP30 enzyme reduces mitochondrial clearance by blocking ubiquitin and preventing its "marking" function. Imbalances in USP30 are associated with a variety of diseases, including mitochondrial diseases and neurodegenerative diseases. A large accumulation of mutations leads to incompatibility, causing mitochondrial dysfunction and negatively impacting health. However, some milder mutations, which also cause disease, are ignored by the cell and not cleared. This complex mechanism was previously poorly understood.

Researchers have now demonstrated in vivo that cells respond to mtDNA mutations by inactivating the labeling effect of ubiquitin, rather than activating new biosynthetic pathways.

Using mice, scientists found that mutations are not perceived in the first few days after fertilization. This is because USP30 is overactivated, inhibiting ubiquitin labeling of defective mitochondrial DNA and blocking its clearance. This leads to an increase in mitochondrial mass and genome size, allowing disease-causing mutations to be passed on.

In the study, the team confirmed that using the inhibitory compound CMPD39 to block USP30 can create a "clearance window" for altered mitochondrial DNA shortly after fertilization. During this period, the embryo naturally clears paternal mitochondria. Unlike nuclear DNA, mtDNA is passed on only by the mother.

Figure 1. Inhibition of the UPS impairs mitochondrial ubiquitination at high heteroplasmy levels. (Frison M, et al., 2025)

Scientists have proposed two possibilities: treating early embryos after in vitro fertilization to reduce the number of cells with high mutational load before implantation; and treating or preventing rare genetic diseases affecting approximately one in eight thousand people through targeted therapy for USP30.

"Mitochondrial diseases can lead to devastating disabilities and even prevent some families from having children," said Patrick Chinnery, Professor of Neurology at the University of Cambridge and the corresponding author of the article. "The UK has approved a new form of in-vitro fertilization to prevent its transmission, but beyond that, we cannot prevent these diseases, and there are few treatments available. Our findings point to a possible new drug therapy that may help stop these diseases in the future, allowing families to have healthy children."

Marcos Roberto Chiaratti, Professor at the Federal University of São Carlos and the sole Brazilian author of the article, added, "We know that this technology involving mitochondrial replacement is controversial and is currently only approved in the UK and Australia. Through our research, we show that there are other possibilities, primarily pharmacological, to treat embryos and prevent the transmission of such diseases."

Reference

Frison M, et al. Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations. Science, 2025, 390(6769): 156-163.