Science in the Triangle

In search of new medicines, researchers have gone inside the cell to study mitochondria, tiny power plants that are key to cellular life and death, and their role in causing disease.

Malfunctioning mitochondria have been linked to cancer, immune defects, neurodegenerative diseases such as Parkinson’s and Alzheimer’s, sterility and deafness. North Carolina scientists have been among those on the forefront of mitochondrial research, including a group at the National Institute of Environmental Health Sciences in Research Triangle Park.

Gerald Shadel

On Tuesday, the NIEHS group hosted Gerald Shadel, a Yale University biochemist who is sort of a mitochondrion whisperer. His lab at Yale’s school of medicine tries to understand how mitochondria tell cells what to do and what happens when the communication breaks down.

“There’s a lot going on here,” Shadel said about the relationship between cells and mitochondria. “I’m going to tell you three stories.”

Mitochondria generate adenosine triphosphate, or ATP, from the food we eat and the air we breathe. ATP carries energy to, for example, power muscle cells to contract, nerve cells to generate electricity and immune cells to protect the body from disease-causing invaders.

To do its job inside of a cell, a mitochondrion is guided by its own genes. Mitochondrial DNA is passed down from mother to child and is separate from a cell’s DNA. In a way, mitochondria are cells within a cell, separate but inseparable. When the relationship goes well, enzymes inside the inner membrane make sure mitochondrial DNA is replicated correctly. When replication mistakes happen, they are repaired. The cell receives the right amount of ATP and clear signals what to do with it.

Aging is part of this cycle. It is brought on by oxidative stress. Byproducts from generating ATP, such as free radicals, cause the stress. Environmental factors can make a cell’s life a lot more stressful. Those factors include cigarette smoke, car emissions, asbestos, infections and excessive amounts of alcohol.

But when researchers in Shadel’s lab tinkered with one gene in the mitochondrial DNA, they were able to lower the oxidative stress and delay cellular aging.

Quieting down the gene’s signaling basically prompted mitochondria to burn cleaner, which damaged cells less, Shadel said. So far, researchers have successfully extended the life span of worm, yeast and mouse cells.

In another story Shadel told, things quickly go wrong in cells because of a mutation in the mitochondrial DNA that not only raises oxidative stress but also hampers mitochondria’s ability to repair replication mistakes in their genetic information.

About 400 mutations in mitochondrial DNA are known to lead to diseases. The onset of the disease appears to depend on which cells are affected. Ataxia telangiectasia is an immunodeficiency disease that affects several organs. It’s a rare disease but first signs appear in childhood. A-T is progressive and most sufferers die from recurrent infections by the time they are in their twenties.

A-T depletes the number of DNA copies in mitochondria, leading to mitochondrial dysfunction. Shadel suggested that after responding normally to initial infections, the immune system of A-T patients slowly breaks down as cells that remember immune responses to disease-causing intruders die because of the mitochondrial dysfunction.

Shadel’s lab also contributed to his third story, which dealt with maternally inherited deafness. The irreversible hearing loss is brought on by a mutation in mitochondrial DNA that affects hair cells in the inner ear. The hair cells are crucial to allow the auditory nerve to function.

But the mutation leads to a chemical signal that causes the hair cells to die, Shadel said.