Research discovers potential new target and drug candidate for Barth syndrome

In a Natural metabolism In this article, researchers from the University of Pittsburgh detail a potential new target and small molecule drug candidate to treat Barth syndrome, a rare, life-threatening and currently incurable genetic disorder with devastating consequences.

Barth syndrome affects approximately 1 in 300,000 to 400,000 babies born worldwide. People with this condition have weak muscles and hearts and suffer from debilitating fatigue and recurring infections.

Pitt researchers have discovered that faulty mitochondria are at least partly to blame and have identified a molecular culprit that could be targeted to potentially reverse the course of the disease in the future.

In healthy people, a lipid called cardiolipin, or CL, undergoes a series of transformations, called remodeling, within the mitochondria, explains the study’s lead author, Dr. Valerian Kagan, professor of environmental health and at work at the University of Pittsburgh School. of Public Health.

However, in people with Barth syndrome, a crucial gene housed in the mitochondria, called tafazzin (TAZ), is mutated. Without TAZ, CL remodeling is stopped dead in its tracks and harmful lipids accumulate.

For this latest investigation, the team used computer models as well as in vitro studies on mouse myoblast cells and human heart tissue samples from people with Barth syndrome.

“We discovered that lyso-cardiolipin, an intermediate that accumulates in TAZ-deficient mutant cells, interacts with the mitochondrial protein cytochrome c, converting it into a demonic enzyme that oxidizes everything around it,” said Kagan.

It turns out that this excessive oxidation in TAZ-deficient cells could be avoided. The team showed that a compound known as imidazole-substituted oleic acid, or IOA, could block the formation of these complexes and improve motor function and endurance in a fruit fly model of the Barth syndrome.

In the future, this discovery may pave the way for correcting genetic tafazzin deficiency and improving mitochondrial function through small molecule therapies.