Restoring cellular energy signals may treat mitochondrial diseases in humans

April 15, 2015, Children's Hospital of Philadelphia
In this mutant worm, about 1/20 of an inch long, green flourescence marks areas of biological stress from malfunctioning mitochondria. Credit: The Children's Hospital of Philadelphia

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

Mitochondria are present in up to several hundred copies 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 human aging.

"This work carries strong promise for identifying effective therapies for ," said study leader Marni J. Falk, M.D., director and attending physician in the Mitochondrial-Genetic Disease Clinic at The Children's Hospital of Philadelphia (CHOP). "The drugs we used in this study improve cellular signaling in ways that could directly benefit patients. As all but one of the drugs are currently prescribed for other diseases, they're already available to now test in clinical trials in patients with mitochondrial disease."

Falk and colleagues published their study online March 3 in the journal Mitochondrion.

The current research 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, common culprits in many , 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 often-severe energy shortages in the heart, brain, eyes, muscles and many other parts of the body.

In the current study, Falk and colleagues studied with mutations that disrupt their mitochondria and make them a useful laboratory model for investigating mitochondrial disease. Using these nematodes, called Caenorhabditis elegans, Falk's research laboratory has done extensive studies to understand mitochondrial disease and potential therapies.

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 Falk. "We're restoring the ratio of critical metabolic precursors and products that control signaling pathways, thereby improving overall cellular health in respiratory chain diseases."

Mitochondrial diseases, she added, are highly complex, but her team's series of nematode studies have revealed fundamental conserved processes that are disrupted in mitochondrial disease. The study team carefully deciphered many of the biological mechanisms at work, marked by changes in oxidant levels, genome expression patterns and other major physiological effects. "Although some specific mechanistic details may differ, we're looking at how the effects of different drugs may converge to promote an organism's health and survival," she said.

Falk and colleagues are now planning a pilot clinical trial in children with complex I deficiencies 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," she added.

Explore further: Central signaling response found in mitochondrial energy diseases

More information: Shana McCormack et al, "Pharmacologic targeting of sirtuins and PPAR signaling improves longevity and mitochondrial physiology in respiratory chain complex I mutant Caenorhabditis elegans," Mitochondrion, published online March 3, 2015 and in May 2015 print issue. doi.org/10.1016/j.mito.2015.02.005

Related Stories

Central signaling response found in mitochondrial energy diseases

July 24, 2013
Researchers 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 ...

Animal results may pave way to treating rare mitochondrial diseases in children

May 19, 2011
A human drug that both prevents and cures kidney failure in mice sheds light on disabling human mitochondrial disorders, and may represent a potential treatment in people with such illnesses.

Energizing sick mitochondria with vitamin B3

April 7, 2014
Vitamins B have recently been turned out to be potent modifiers of energy metabolism, especially the function of mitochondria.

Study reveals possible treatment for diseases caused by Mitofusin 2 deficiency

February 16, 2015
Researchers have discovered a novel role for Mitofusin 2, and the findings may point to a new treatment for patients with diseases caused by loss of the mitochondrial protein. The study appears in The Journal of Cell Biology ...

Scientists create one-step gene test for mitochondrial diseases

January 29, 2013
More powerful gene-sequencing tools have increasingly been uncovering disease secrets in DNA within the cell nucleus. Now a research team is expanding those rapid next-generation sequencing tests to analyze a separate source ...

Recommended for you

Gut bacteria play key role in anti-seizure effects of ketogenic diet

May 24, 2018
UCLA scientists have identified specific gut bacteria that play an essential role in the anti-seizure effects of the high-fat, low-carbohydrate ketogenic diet. The study, published today in the journal Cell, is the first ...

New blood test to detect liver damage in under an hour

May 24, 2018
A quick and robust blood test that can detect liver damage before symptoms appear has been designed and verified using clinical samples by a team from UCL and University of Massachusetts.

Selective neural connections can be reestablished in retina after injury, study finds

May 24, 2018
The brain's ability to form new neural connections, called neuroplasticity, is crucial to recovery from some types of brain injury, but this process is hard to study and remains poorly understood. A new study of neural circuit ...

Space-like gravity weakens biochemical signals in muscle formation

May 23, 2018
Astronauts go through many physiological changes during their time in spaceflight, including lower muscle mass and slower muscle development. Similar symptoms can occur in the muscles of people on Earth's surface, too. In ...

Eating at night, sleeping by day swiftly alters key blood proteins

May 21, 2018
Staying awake all night and sleeping all day for just a few days can disrupt levels and time of day patterns of more than 100 proteins in the blood, including those that influence blood sugar, energy metabolism, and immune ...

Hotter bodies fight infections and tumours better—researchers show how

May 21, 2018
The hotter our body temperature, the more our bodies speed up a key defence system that fights against tumours, wounds or infections, new research by a multidisciplinary team of mathematicians and biologists from the Universities ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.