Investigators Discover Mitochondrial Signaling Response

Researchers from Children’s Hospital have identified a master network of signaling molecules that acts like a “fuse box” to regulate the cellular effects of defective energy flow in mitochondrial respiratory chain diseases — a diverse set of difficult-to-treat genetic-based energy disorders. Using that knowledge, they showed that a form of vitamin B3 called nicotinic acid partially restores normal functioning in cells taken from patients with mitochondrial disease.

The study, which was led by Marni J. Falk, MD, suggests that the regulatory signaling network may offer a common avenue to target in developing effective, personalized treatments for many mitochondrial energy disorders. Dr. Falk and her colleagues published their study in the journal PLOS ONE.

Primary mitochondrial diseases directly interfere with the function of the respiratory chain (RC) — the highly conserved sequence of chemical reactions within mitochondria that generate energy from oxygen and nutrients. RC malfunction in mitochondrial disease may cause symptoms such as seizures, strokes, blindness, heart disease, progressive muscle weakness, and vulnerability to infections. No cure exists, and most current treatments for RC diseases are largely ineffective.

In the current study, Dr. Falk and her team analyzed cellular responses in human skeletal muscle and skin cell lines, finding that RC disease disrupted crucial biological pathways controlled by a handful of master signaling factors. All of those factors are integral components of cellular signaling networks that sense nutrient availability and regulate growth.

Building on her team’s previous studies, Dr. Falk and colleagues used a form of vitamin B3, nicotinic acid, in their current study. They added nicotinic acid to a cell line grown from the skin of a patient with the mitochondrial disease known as Leigh syndrome that causes strokes in young children.

The results were exciting. The nicotinic acid normalized signaling activity across an integrated signaling network, and also improved overall cellular respiration — the cells’ ability to use oxygen.