Mitochondrial Disease Signaling Network Discovered

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

The study, which was led by Marni J. Falk, MD, director and attending physician in the Mitochondrial-Genetic Disease Clinic, suggests that the regulatory signaling network may offer an avenue to target in developing effective, personalized treatments for many mitochondrial energy disorders. Dr. Falk and her colleagues recently published their study in PLOS ONE.

Mitochondria are tiny biological structures that act as our cell’s power plants, extracting energy from nutrients to drive the body. When mitochondria malfunction, they can impair the function of potentially any organ in the body, in a bewildering variety of ways.

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 respiratory chain diseases are largely ineffective.

In the current study, Dr. Falk and her team including first author Zhe Zhang, PhD, of CHOP’s Center for Biomedical Informatics, analyzed cellular responses in human skeletal muscle and skin cell lines, finding that respiratory chain disease disrupted crucial biological pathways. Building on previous work showing that a cholesterol-lowering drug called probucol restored kidney function in a mouse model of an RC defect, the investigators added a form of vitamin B3, 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. “There are hundreds of different individual reasons for RC malfunction,” said Dr. Falk, “but we identified a common cellular response — an integrated, nutrient-sensing signaling network — that recognizes when energy flow is impaired.

While researchers have yet to determine if this discovery might lead to clinical treatments, “finding a central signaling mechanism common to highly diverse RC disease should allow researchers to better classify subtle differences in this signaling response to understand subtypes mitochondrial disease and fashion personalized treatments that restore specific signaling alterations identified in individual patients,” Dr. Falk said.

To read the full study, see PLOS ONE.