Restoring Cellular Energy Could Lead to Mitochondrial Disease Treatments

Rooted in malfunctions in the power plants that energize our cells, mitochondrial disorders are notoriously complex, with few effective treatments. Now, novel findings published recently in the journal Mitochondrion may hold great promise for children and adults with mitochondrial disorders. By using existing human drugs to improve metabolism and restore shortened lifespans in microscopic worms, scientists have set the stage for human clinical trials of possible innovative therapies for mitochondrial disease.

Mitochondria are present in nearly every cell, but when they don’t work properly, they impair many systems in the body by short-circuiting normal energy flow. While primary mitochondrial disorders are individually rare, hundreds of them exist, collectively affecting at least one in 5,000 individuals. Abnormal mitochondrial functions also play important roles in common conditions such as type 2 diabetes, epilepsy, Alzheimer’s disease, and even aging.

“This work carries strong promise for identifying effective therapies for mitochondrial diseases,” said The Children’s Hospital of Philadelphia’s Marni J. Falk, MD, director of CHOP’s Mitochondrial-Genetic Disease Clinic and leader of the Mitochondrion study. “The drugs we used in this study improve cellular signaling in ways that could directly benefit patients.”

The researchers’ investigation focuses on the respiratory chain, a set of five enzyme complexes that together are a crucial site of energy production inside mitochondria. In respiratory chain (RC) defects, cells fail to properly produce energy. The most common site of RC dysfunction is complex I, a group of proteins that normally generates a key metabolic product, nicotinamide adenine dinucleotide (NAD+).

NAD+ normally regulates hundreds of other chemical reactions within the cell. When genetic mutations disrupt complex I proteins and the metabolic conversion of NADH to NAD+, patients may suffer severe energy shortages in the heart, brain, eyes, muscles, and many other parts of the body.

In their Mitochondrion paper, Dr. Falk and colleagues studied microscopic worms, called Caenorhabditis elegans, with mutations that disrupt their mitochondria and make them a useful laboratory model for investigating mitochondrial disease. The researchers tested a series of drugs currently used to treat patients with diabetes or lipid disorders. One drug, nicotinic acid, is a form of niacin (vitamin B3) that has been used for decades to treat patients who have high triglycerides in their blood.

The C. elegans worms had mutations that directly impaired their complex I function and shortened their lifespans. Nicotinic acid restored the worms’ lifespans to that of normal animals. It also restored the levels of NADH, enabling it to play its crucial role of initiating the transport of electrons in the RC that is necessary to produce cellular energy, as well as regulating many other cellular processes.

The team showed that other available human drugs also improved key metabolite levels in C. elegans. “In contrast to research that aims to repair defective mitochondria, we are bypassing the damaged mitochondria and focusing instead on how cells respond to mitochondrial problems,” said Dr. Falk.

Dr. Falk and colleagues are now planning a pilot clinical trial in children to determine whether the effects seen in the animals will translate to meaningful clinical benefits in patients. Ultimately, she expects the complexity of mitochondrial biology will dictate that effective treatments will require combination therapies specific to restoring signaling pathways that are commonly disrupted in major subtypes of mitochondrial disease.

“We’re enthusiastic that we have reached a major threshold on the path toward bringing important new therapies to a very challenging group of diseases,” Dr. Falk added.