New Potential Therapeutic Approach for Mitochondrial Diseases Based on Mitochonic Acid 5

A team led by researchers at Tohoku University Graduate School of Medicine in Japan recently discovered a compound able to improve the survival of cells from patients with mitochondrial diseases, offering a new potential therapeutic approach. The study is entitled “Mitochonic Acid 5 (MA-5), a Derivative of the Plant Hormone Indole-3-Acetic Acid, Improves Survival of Fibroblasts from Patients with Mitochondrial Diseases” and was published in The Tohoku Journal of Experimental Medicine.

Mitochondria are small cellular organelles in the body responsible for the production of energy (in the form of ATP) through the process of respiration; mitochondria are also involved in the regulation of apoptosis (cell death) and several signaling pathways. Mitochondrial diseases are caused by mitochondrial dysfunction due to mutations in genes expressed in the mitochondria.

Mitochondrial dysfunction can cause impairment in cellular energy metabolism, which can potentially affect several organs and systems like the brain, heart and muscles. Mitochondria are also a major site for the generation of reactive oxygen species (ROS), which, when present in high levels, can induce significant damage to cell structures. Mitochondrial dysfunction creates an imbalance between ROS production and their neutralization through antioxidant systems (a phenomenon known as oxidative stress), which can lead to the development of medical disorders.

Indole-3-acetic acid (IAA) is a plant hormone that is also synthesized in mouse liver and kidney, and in intestinal anaerobes. IAA has been shown to increase the growth of mouse and human fibroblasts (the most common cells of the connective tissue in animals), although the underlying mechanism has not been elucidated.

In the study, researchers screened a chemical library composed of IAA analogs to search for compounds able to increase the cellular ATP levels, and that therefore could potentially improve mitochondrial dysfunction.

Researchers identified a potential drug capable of enhancing ATP production – mitochonic acid 5 (MA-5), 4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid. MA-5 was found to improve the survival of fibroblasts collected from patients with mitochondrial diseases, including Leigh syndrome, MELAS (myopathy encephalopathy lactic acidosis and stroke-like episodes), Leber’s hereditary optic neuropathy and Kearns-Sayre syndrome. The researchers believe that the improved survival rate observed is linked to the increased cellular levels of ATP.

The research team concluded that MA-5 could be considered a potential therapeutic drug for mitochondrial diseases. This potential therapeutic option is important as its mechanism of action differs from the current anti-oxidant therapies being exploited.