Improving ATP Production in Mitochondrial Diseases
Duchenne Muscular Dystrophy. Organ trauma. Genetic myopathies.
These conditions, and countless others, have myriad differences, but they’re all characterized by adenosine triphosphate (ATP) depletion—reduced energy availability.
A UCLA research team led by Orian Shirihai, MD, PhD, recently identified a way to inhibit ATP depletion using an unlikely weapon: chocolate.
Specifically, they identified a molecule derived from chocolate with promise for blocking ATP depletion, and consequently, improving disease outcomes.
Read the full study in The Embo Journal
How Does ATP Synthase Produce ATP?
ATP is the universal currency of energy. Double-membraned organelles called mitochondria create ATP by processing nutrients in two units:
- A combustion unit that burns nutrients and uses the resulting energy to charge a battery.
- An electrical engine unit that, under the direction of a protein called ATP synthase, uses the battery’s charge to make ATP.
“The mitochondria combust nutrients and use the energy of combustion to electrically charge its membrane,” Shirihai explains. “It then uses the electrical charge to spin the turbine and produce ATP. In a way, mitochondria are like a hybrid car, combining an engine with a battery. The engine burns the fuel to spin a turbine to charge a battery.”
Recent studies have transformed collective understanding of ATP production by demonstrating that ATP synthase, which produces ATP, has the ability to work in reverse—consuming ATP instead of producing it.
The team discovered that the reverse action can be found in healthy mitochondria but is aggravated in diseased cells.
“We never considered that within an individual mitochondrion, ATP production and elimination can occur simultaneously by multiple ATP synthase units working in opposite directions. This is like having a car where the front wheels run forward and the back wheels run backward.”
What Is ATP Hydrolysis?
ATP hydrolysis is the reverse function of ATP synthase, the process through which the car’s wheels run backward instead of forward.
“When that happens, ATP is cleaved back to ADP and phosphate and the energy is lost,” Shirihai explains. “Cleaving ATP to ADP and phosphate is ATP hydrolysis.”
ATP hydrolysis results in energy loss.
The Therapeutic Benefits of Epicatechin in Muscle Cells
Fascinated by this newly defined reverse action of ATP synthase, Shirihai’s team set out to stop it. They ultimately identified a family of compounds derived from chocolate, which bind to ATP synthase.
Epicatechin proved the most promising of these chocolate-derived compounds.
Given to cells derived from patients suffering from mitochondrial diseases, Epicatechin effectively prevented the reverse activity of ATP synthase, thereby inhibiting ATP hydrolysis and depletion.
“This is a paradigm shift for mitochondrial diseases," says Dr. Shirihai. "When developing treatments for mitochondria diseases, we always aimed at repairing the machinery responsible for nutrient combustion, called “The Respiratory Chain”. Here we find that, in some diseases, energetic state of the cell can be improved by simply inhibiting ATP hydrolysis, even without repairing the respiratory chain.”
The research team compared what they accomplished with Epicatechin to patching a bike tire.
“ATP depletion is like having a puncture in a bike tire, where the air (the ATP) is being released and you cannot bike properly,” Shirihai says. “Epicatechin acts as a patch, preventing the air from escaping, and thus allowing you to finish your bike ride.”
Mitochondria, Muscle Force and a Major Breakthrough?
These promising early results inspired the team to see if Epicatechin could mitigate ATP depletion in other disease models.
They started with a model of Duchenne Muscular Dystrophy (DMD). DMD involves a progressive reduction in muscle force, which impedes basic motor control and essential muscle function, eventually leading to early death.
In the model, treatment with Epicatechin resulted in recovery of the muscle force and prevention of muscle cell death.
The results establish the novel therapeutic potential of targeting the machinery driving ATP depletion to improve outcomes in the diseases associated with it.