August 2013

Children’s Hospital Investigators Discover Mitochondrial Signaling Response


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 may impair the function of potentially any organ in the body, in a bewildering variety of ways. Mitochondrial disease can have widely varying effects and severity, ranging from blindness to exercise intolerance to death, often wreaking progressive havoc over time in both children and adults.

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, director and attending physician in the Mitochondrial-Genetic Disease Clinic, suggests that the regulatory signaling network may offer a common avenue to target in developing effective, personalized treatments for many mitochondrial energy disorders.

“Finding a common cellular response reveals that some order exists in the chaos of these basic energy diseases,” said Dr. Falk. “Identifying the central factors regulating manifestations of mitochondrial disease is like troubleshooting a household electrical system: instead of analyzing problems that may occur at each individual light bulb or switch plate, we have located a central problem in the fuse box.”

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.

“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. That response alters a host of biological pathways, and in many tissues, those secondary biochemical changes are actually contributing to the symptoms of disease.”

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, including FOXO, PPAR, sirtuins, AMPK, and mTORC1. All of those factors are integral components of cellular signaling networks that sense nutrient availability and regulate growth.

“The good news in our research is that the signaling pathways regulating the body’s response to mitochondrial disease are already well-known for other reasons,” said Dr. Falk. “Using an agent that restores their collective activity toward more normal functioning offers potential treatments for the diverse symptoms of mitochondrial RC disease.”

Building on her team’s previous animal studies, which showed that a cholesterol-lowering drug called probucol restored kidney function in a mouse model of an RC defect, Dr. Falk and colleagues used a form of vitamin B3, nicotinic acid, in their current study. Like probucol, nicotinic acid is known to stimulate the PPAR signaling pathway. Here, 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 not just in PPAR, but across an integrated signaling network, and also improved overall cellular respiration — the cells’ ability to use oxygen. “Even though the underlying genetic defect in RC function persisted, we were able to reverse some of its major deleterious downstream effects on crucial cellular functions that are impaired in many varieties of mitochondrial disease,” Dr. Falk noted.

More work remains to be done to determine if this discovery in patient tissues and cell culture may lead to effective clinical treatments. Nonetheless, “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.

Dr. Falk and her colleagues published their study in the journal PLOS ONE.

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