Specific Compound Boosts Energy Output in Mitochondrial Disease Cells, Study Finds

A mitochondria-targeting compound called mitochonic acid (MA-5) had beneficial effects on mitochondrial function, energy production, and the formation of oxidative molecules in experiments involving a mouse model of mitochondrial disease and cells from patients.

The study also identified a biomarker of mitochondrial disease and the response to MA-5 — a crucial finding that allows patient selection and robust measurements in future clinical trials of the compound. The study, “Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases,” was published in the journal EBioMedicine.

The Japanese research team from Tohoku University Graduate School of Medicine had previously studied the compound in cells from a number of mitochondrial diseases, including Leigh syndrome, MELAS, and Kearns-Sayre syndrome.

But they figured that many mitochondrial mutations affect energy-making parts called the electron transfer complex (ETC) and ATP synthase, a molecular complex in the mitochondria that creates the energy storage molecule adenosine triphosphate.

To examine whether the compound affects energy production, they gathered fibroblast cells (the primary active cells in connective tissue) from 25 patients with different mitochondrial mutations. MA-5 had protective properties in cells from 24 of the 25 patients, preventing cell death when researchers exposed the cells to a mitochondria-damaging compound.

The research team also found that the mitochondrial compound GDF-15 could serve as a marker for mitochondrial disease. It was increased in the blood serum of 17 patients who had a blood test. GDF-15 was also increased in cells from patients.

When researchers treated the cells with the mitochondria-damaging agent, GDF-15 levels rose in accordance with the dose of the damaging chemical. But when cells were treated with MA-5, the levels dropped.

This is an important observation, since to study MA-5 in future clinical trials, researchers need effective markers of its effectiveness. Such markers are also crucial for the selection of participants likely to respond to the compound.

The team further tested MA-5 in a mouse model of mitochondrial disease. GDF-15 was also increased in these animals, but experiments indicated that it became lower through MA-5 treatment.

The compound also lowered the production of so-called radical oxygen species, and increased levels of ATP, a molecule that provides cells with energy. The appearance and dynamics of mitochondria also improved after treatment with MA-5.

Their findings indicate that MA-5 may be a promising candidate not only for treating mitochondrial disease, but also for the treatment of other conditions related to mitochondrial health, such as diabetes and heart disease.