Repairing Cellular Powerhouses

by Melia D. Matthews

Every muscle cell in our bodies has hundreds of mitochondria, tiny subcellular powerhouses that transform complex molecules like sugars into energy. Muscle cells are especially energy-hungry: they need fuel to contract and keep our bodies moving. More mitochondria are found in muscle than in many other cell types. When mitochondria aren’t functioning correctly, muscle cells are one of the first places where problems become apparent.

Because muscle cells are rich in mitochondria and especially sensitive to mitochondrial dysfunction, they have become a focus of intense investigation for Kaydine Edwards, a doctoral student who studies mitochondrial disease in the lab of Joeva Barrow, Nutritional Science.

One in 5,000 people suffers from mitochondrial disease, experiencing a wide range of symptoms from muscle weakness to seizures. Scientists have a pretty good idea as to why mitochondrial disease occurs—mutations in mitochondrial genes are often to blame—but very few treatments are available.

Protein Complexes and the Electron Transport Chain

A key piece of machinery at the core of the mitochondrial powerhouse is the electron transport chain. To understand it, think of a bucket brigade: people in a line passing buckets of water from one person to the next to put out a fire. But the mitochondrial bucket brigade is a crew of proteins, and instead of buckets, they pass electrons. As the proteins, also called complexes, pass electrons down the line, they simultaneously pump positively charged ions to a distinct location within the mitochondria. The electron transport chain thereby generates an electrochemical gradient. When the ions flow back to their original location within the mitochondria, they create energy in the form of adenosine triphosphate (ATP), the basic energy currency of a cell. Through this efficient method of electron pass-along, the electron transport chain can turn one sugar molecule into 36 ATP molecules.

A mutation in one protein complex in the electron transport chain can cause disease. In fact, each dysfunctional complex may lead to a distinct disease. Treatments need to be identified for each one. “The big-picture question is, can we find a small biomolecule to rescue diseased cells?” Edwards says.

“We are teasing apart perturbations in [the complexes of the electron transport chain] to see if we can facilitate a cellular rescue.”

Saving Complex IV

To develop new and better treatments for mitochondrial disease, Edwards is identifying biomolecules that might rescue the electron transport chain’s delicate molecular machinery. Her project focuses specifically on disease involving Complex IV, otherwise known as cytochrome c oxidase.

“We are teasing apart perturbations in [the complexes of the electron transport chain] to see if we can facilitate a cellular rescue using a high-throughput screen with different biomolecules,” Edwards says. She mutates Complex IV in a cell model, causing the cells to replicate the effects of mitochondrial disease. She then tests a wide range of biomolecules to see if they can rescue the cells. “We have a library of [800] various small biomolecules that are previously unstudied, and we are hoping to identify one or two or more that can improve the function of the Complex IV–deficient cells,” Edwards says.

Starting with muscle stem cells from murine models, Edwards uses a tool called Cre-loxP to alter a genetic sequence that codes for Complex IV. With Complex IV disrupted, the so-called knock-out cells proliferate slowly. “Mitochondrial disease happens because there is some sort of disruption in the mitochondria’s ability to produce energy, which translates to our cells proliferating at a slower rate compared to healthy cells,” Edwards says.

Edwards measures the proliferation rate of the knock-out cells. She then adds various biomolecules and assesses the cells again. “We are looking for small biomolecules that can essentially increase the regenerative capacity in the knock-out cells,” Edwards says. “Our hope is that the positive candidates from the screen can stimulate the stem cell pool to proliferate, differentiate, and create new, healthy muscle tissue that can replace the diseased tissue.”

Once Edwards has identified promising biomolecules, the Barrow lab will investigate the molecular mechanisms behind mitochondrial disease. The hope is one day to translate the lab’s cellular-level research into treatments for humans.

Barrow, the principal investigator on Edwards’s project, describes her student as a passionate and motivated team player: “I am extremely fortunate to have [Edwards] with my group,” Barrow says.

Edwards is the first member of her family to pursue a graduate degree. She has always been interested in making an impact on public health, and she credits the Research Initiative for Scientific Enhancement (RISE) program with introducing her to research. A program of the National Institutes of Health, RISE helps underrepresented students in science pursue careers in biomedical fields.

Edwards plans to expand her applied nutrition background and work toward her Registered Dietitian credentials after attaining a PhD, building on her interests in nutrition, metabolism, and human health. “I want to use the knowledge gained from my research to affect nutrition and health policy in my career,” she says. She plans to bring the scientific knowledge that she is developing in the realm of mitochondrial disease into new policy initiatives that can help people live healthier lives.

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