Can mitochondria produce more energy without collateral damage?

Is it possible to increase mitochondrial energy production without also increasing potentially harmful byproducts? If so, such a method could be used to treat a multitude of neurodegenerative diseases in which altered mitochondria would play a central role.

In search of the answer, a team of Gladstone Institutes scientists used CRISPR gene-editing technology to analyze exactly which molecules are responsible for creating energy versus those that control the production of reactive species of the Oxygen, or ROS, toxic byproducts commonly called “free radicals.”

Their conclusions, which appear in Proceedings of the National Academy of Sciencescould lead to strategies for decoupling energy from ROS production, which could help in the development of therapies for diseases such as Parkinson’s or Alzheimer’s.

“Understanding how to separate energy production from ROS production is really critical to treating mitochondrial dysfunction,” says Gladstone researcher Ken Nakamura, MD, Ph.D., who led the study. “There are many pathologies, including neurodegeneration, where increasing mitochondrial energy could be beneficial, but we don’t want to damage cells with toxic byproducts.”

When mitochondria generate cellular energy from sugars and fats, they release ROS. Much like pollution released from a power plant, ROS have long been considered undesirable but difficult to prevent byproducts.

Although ROS perform some important biological functions, their presence in excess is toxic to cells and linked to many chronic and degenerative diseases.

The imbalance at the origin of the disease

Solving the question of how to help mitochondria work more efficiently could contribute to new therapeutic approaches for neurodegeneration and diseases such as heart disease, diabetes and cancer. This even has implications for healthy aging, as mitochondria become defective as we age.

However, in many cases it is difficult to understand exactly how mitochondria are malfunctioning: are they not producing enough cellular energy or are they producing too much ROS?

Nakamura’s group previously examined cells to discover all the genes involved in regulating energy levels. In their new work, they focused on around 200 of these genes. Using CRISPR, they worked on cancer cells to selectively knock down the expression of each of these genes and studied what happened to ROS levels.

“We wanted to determine which molecules are necessary for energy production or ROS production,” explains scientist Neal Bennett, first author of the new study. PNAS study. “By doing this, we were able to discern genes and pathways that can modify these systems independently, which could be very useful in treating diseases.”

Indeed, although some genes affect both energy and ROS production, others have a much stronger effect on one product than the other.

Overall, these results provide an interesting starting point for researchers interested in developing drugs that independently control mitochondrial energy and ROS, as well as for those trying to understand how mitochondrial dysfunction is involved in disease.

The team plans to conduct more research on the impact of changing ROS levels on cellular health and determine whether their findings hold for other cell types, including brain cells.