Research reveals possibility of new drug therapy for hereditary diseases

A study published in Science and involving a Brazilian researcher unveils a cellular mechanism involved in transmitting mutations in mitochondrial DNA. These mutations can cause serious, incurable diseases.

By Luciana Constantino  |  Agência FAPESP – A study published in the latest issue of Science reveals a cellular mechanism involved in the inheritance of genetic mutations. The study also points to a potential treatment that could reduce the risk of babies being born with serious, incurable mitochondrial diseases.

According to the group’s findings, the transmission of these alterations involves a process that blocks the elimination of mutant mitochondria while increasing their number in cells. This explains how these variants “escape” selection and can cause diseases in the future.

Mitochondria are the main source of energy in all cells and have their own DNA. Shortly after fertilization, the embryo has a “quality control” system that eliminates “defective” mitochondria, a process called mitophagy. During this process, the protein ubiquitin acts as a marker that directs altered molecules to destruction.

Mitophagy maintains harmony between mitochondrial DNA (mtDNA) and nuclear DNA, ensuring compatibility between the two. However, because mtDNA mutates at a rate approximately 15 times higher than the nuclear genome, this poses a challenge to their symbiotic relationship.

The enzyme USP30 (short for ubiquitin-specific protease 30) acts on ubiquitin by blocking it and preventing “labeling,” which reduces elimination. Imbalances in USP30 have been linked to several diseases, including mitochondrial and neurodegenerative diseases. A large accumulation of mutations results in incompatibility, causing mitochondrial dysfunction and negative health effects. This process is well documented in the scientific literature.

However, there are milder mutations that also cause disease but go unnoticed and are not eliminated by cells. This complex mechanism was poorly understood.

The results

Researchers have now demonstrated in vivo that cells respond to mtDNA mutations by deactivating the marker effect of ubiquitin instead of activating new biosynthetic pathways.

Using mice, the scientists discovered that mutations are not perceived in the first days after fertilization because USP30 is overactivated, which inhibits ubiquitin from marking defective mitochondrial DNA and blocking its elimination. This results in an increase in mitochondrial mass and genome, which allows the transmission of mutations that can cause diseases.

In the study, the group demonstrated that preventing USP30 from acting with the inhibitor Compound 39 (CMPD39) creates a “window of elimination” for altered mitochondrial DNA shortly after fertilization. During this period, the embryo naturally eliminates paternal mitochondria. Unlike nuclear DNA, where children inherit half from each parent, mtDNA is transmitted solely from the mother.

In the study, the scientists proposed two possibilities: treating early embryos after in vitro fertilization to reduce the number of cells with a high mutational load before implantation and targeting USP30 therapeutically to treat or prevent rare hereditary diseases that affect about one in eight thousand people.

“Mitochondrial diseases can cause devastating disabilities and even prevent some families from having children. The United Kingdom has approved a new form of in vitro fertilization that can prevent their transmission, but other than that, we have no way of preventing these diseases, and there are few treatments available. Our discovery points to a possible new drug therapy that could help stop these diseases in the future, allowing families to have healthy children,” Patrick Chinnery, a professor of neurology at the University of Cambridge and the corresponding author of the article, told Agência FAPESP.

Recently, a team of researchers at Newcastle University successfully performed an innovative in vitro fertilization technique involving the replacement of mothers’ mutant mitochondrial DNA with mitochondria from healthy donors. The treatment was called mitochondrial replacement therapy. Eight babies – four boys and four girls – were born who may be protected from mitochondrial diseases. The results were published in The New England Journal of Medicine (read the study here: www.nejm.org/doi/full/10.1056/NEJMoa2415539).

“We know that this technique involving mitochondrial replacement is controversial and has only been approved, for now, in England and Australia. With our research, we show that there are other possibilities, mainly pharmacological, to treat the embryo and prevent the transmission of these types of disease,” adds Marcos Roberto Chiaratti, a professor at the Department of Genetics and Evolution at the Federal University of São Carlos (UFSCar) and the only Brazilian author of the article published in Science.

The research received support from FAPESP through a Thematic Project conducted in a joint call with the Biotechnology and Biological Sciences Research Council. Led by Chiaratti with the participation of Chinnery, the project aims to study the molecular mechanisms that modulate the transmission of mtDNA variants through the germline.

What are they?

Mitochondrial diseases are inherited metabolic disorders that affect mitochondrial function, potentially resulting in damage to vital organs such as the brain and heart. The most common include Leber’s hereditary optic neuropathy (LHON), Leigh syndrome, and MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes).

Depending on which cells are affected, symptoms can range from growth problems and cognitive developmental delays to muscle weakness, pain, vision and/or hearing loss, and seizures.

Although there are no specific treatments for these diseases, medication is sometimes used to control the symptoms. Diagnosis is often complex and requires a detailed analysis of the patient’s clinical data, as well as other types of tests, such as muscle biopsies, biochemical analyses, and genetic-molecular testing.

The article “Ubiquitin-dependent mitophagy regulates the inheritance of mitochondrial DNA mutations" can be read at www.science.org/doi/10.1126/science.adr5438.