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"Fixing" energy signals to treat mitochondrial disease

Restoring cellular energy signals may offset mitochondrial diseases in humans. Using existing drugs to treat lab animals, researchers have set the stage for clinical trials.

Malfunctions in the tiny power plants that energize our cells, mitochondrial disorders are notoriously complex and variable, with few effective treatments. Now, experiments with microscopic worms — c elegans — may hold great promise for children and adults suffering mitochondrial disorders.

By using existing human drugs to improve metabolism and restore shortened lifespans in these worms, scientists have set the stage for human clinical trials of possible innovative therapies for mitochondrial disease.

Up to several hundred copies of mitochondria exist in in nearly every cell. When they don't work — they short-circuit energy flow to and within human tissue.

While mitochondrial disorders are rare — hundreds exist — affecting at least one in 5,000 people.

Abnormal mitochondrial function also plays an important role in conditions such as type 2 diabetes, epilepsy, Alzheimer's disease — even aging.

"The drugs we used in this study improve cellular signaling in ways that could directly benefit patients. All but one of the drugs are currently prescribed for other diseases, so they are already available to test in clinical trials in patients with mitochondrial disease," says Marni J. Falk MD, study leader and Director and Attending Physician in the Mitochondrial - Genetic Disease Clinic of the Children's Hospital of Philadelphia (CHOP).

Falk and her colleagues published their study online March 3, 2015 in the journal Mitochondrion.

Current research focuses on the respiratory chain, a set of five enzyme complexes crucial to energy production inside mitochondria.

Respiratory chain defects are common in many mitochondrial disorders failing to produce energy.

Most common site of RC dysfunction — complex 1 — where proteins normally generate a key metabolite, nicotinamide adenine dinucleotide (NAD+).

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

In the study, Falk and her colleagues used microscopic worms with mutations that disrupt their mitochondria. Falk's extensive research with these nematodes, called Caenorhabditis elegans — c elegans — to understand mitochondrial disorders and possible therapies.

Her researchers tested a series of drugs currently used to treat patients with diabetes or lipid disorders. One, nicotinic acid, is a form of niacin (vitamin B3) used for decades to treat patients with high blood triglycerides.

The c elegans tested had mutations impairing their complex 1 function which shortened their lifespans.

Nicotinic acid restored the worms' lifespans to that of normal animals. It also restored levels of NADH.

NADH initiates the transport of electrons into the respiratory chain (RC) for energy production, and ends up regulating many cell processes.

The team also identified other available human drugs that improved key metabolite levels in C. elegans. Says Falk: "In contrast to research that aims to repair defective mitochondria...We're restoring the ratio of critical metabolic precursors and products that control signaling pathways..."

Mitochondrial diseases are highly complex, but Falk's series of c elegans studies have revealed numerous protected cell processes disrupted by mitochondrial diseases. Her researchers deciphered many of the biological mechanisms marked by changes in oxidation levels, genome protein patterns and other physiological effects of mitochondrial disruption.

"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 added.

Falk researchers are now planning a pilot clinical trial in children with complex 1 deficiencies to determine whether the effects seen in animals will translate into meaningful clinical benefits in patients. Ultimately, she expects the complexity of mitochondrial biology will dictate that effective treatments require combination therapies specific to restoring signaling pathways commonly disrupted in major subtypes of mitochondrial disease.

Mitochondrial respiratory chain (RC) diseases are highly morbid multi-systemic conditions for which few effective therapies exist. Given the essential role of sirtuin and PPAR signaling in mediating both mitochondrial physiology and the cellular response to metabolic stress in RC complex I (CI) disease, we postulated that drugs that alter these signaling pathways either directly (resveratrol for sirtuin, rosiglitazone for PPARγ, fenofibrate for PPARα), or indirectly by increasing NAD+ availability (nicotinic acid), might offer effective treatment strategies for primary RC disease. Integrated effects of targeting these cellular signaling pathways on animal lifespan and multi-dimensional in vivo parameters were studied in gas-1(fc21) relative to wild-type (N2 Bristol) worms. Specifically, animal lifespan, transcriptome profiles, mitochondrial oxidant burden, mitochondrial membrane potential, mitochondrial content, amino acid profiles, stable isotope-based intermediary metabolic flux, and total nematode NADH and NAD+ concentrations were compared. Shortened gas-1(fc21) mutant lifespan was rescued with either resveratrol or nicotinic acid, regardless of whether treatments were begun at the early larval stage or in young adulthood. Rosiglitazone administration beginning in young adult stage animals also rescued lifespan. All drug treatments reversed the most significant transcriptome alterations at the biochemical pathway level relative to untreated gas-1(fc21) animals. Interestingly, increased mitochondrial oxidant burden in gas-1(fc21) was reduced with nicotinic acid but exacerbated significantly by resveratrol and modestly by fenofibrate, with little change by rosiglitazone treatment. In contrast, the reduced mitochondrial membrane potential of mutant worms was further decreased by nicotinic acid but restored by either resveratrol, rosiglitazone, or fenofibrate. Using a novel HPLC assay, we discovered that gas-1(fc21) worms have significant deficiencies of NAD+ and NADH. Whereas resveratrol restored concentrations of both metabolites, nicotinic acid only restored NADH. Characteristic branched chain amino acid elevations in gas-1(fc21) animals were normalized completely by nicotinic acid and largely by resveratrol, but not by either rosiglitazone or fenofibrate. We developed a visualization system to enable objective integration of these multi-faceted physiologic endpoints, an approach that will likely be useful to apply in future drug treatment studies in human patients with mitochondrial disease. Overall, these data demonstrate that direct or indirect pharmacologic restoration of altered sirtuin and PPAR signaling can yield significant health and longevity benefits, although by divergent bioenergetic mechanism(s), in a nematode model of mitochondrial RC complex I disease. Thus, these animal model studies introduce important, integrated insights that may ultimately yield rational treatment strategies for human RC disease.

C. elegans, Caenorhabditis elegans; CI, complex I; RC, respiratory chain; NA, nicotinic acid; BCAA, Branched chain amino acid; DMSO, dimethyl sulfoxide

Mitochondrial disease; Nicotinic acid; Resveratrol; Rosiglitazone; Fenofibrate; Transcriptome

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. http://doi.org/10.1016/j.mito.2015.02.005

Funds from the National Institutes of Health (grants HD065858, HD026979, DK094723 and GM097409), the Philadelphia Foundation and the American Heart Association supported this research.

About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 535-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.

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The number of mitochondria in a human cell can vary widely by tissue and cell type.
Red blood cells have no mitochondria, whereas liver cells can have more than 2000.

These human lung mitochondria organelles show their various compartments.
Each performs a specialized function.
Image Credit: Wikipedia


Phospholid by Wikipedia