Enzyme dynamics reveal how mitochondria read their DNA to power cells

Aging, neurological diseases and the response to the stress of our body are all linked to the tiny power plants inside each cell known as mitochondria. To function properly, the mitochondria must first read the instructions of their DNA, then copy them into mRNA in a process called transcription.

Now, researchers at Thomas Jefferson University have reconstructed transcription in human mitochondria in unprecedented details. The results, published in Molecular cellShow how molecular machinery works and reveal potential drug targets for mitochondrial diseases.

“When we understand this key process, we can validate targets for a new class of drugs that restore the mitochondrial potential”, explains the structural biologist and principal author Dmitry Temiakov, pH.D ..

Dr. TEMIAKOV, a member of Sidney Kimmel Medical College, and his laboratory were the first to determine the structure of a key enzyme, known as human mitochondrial Arn Polymérase in 2011. Since then, he and his team have worked to understand the “molecular gymnastics” of the enzyme. He modifies the form and interacts with other proteins in the cell as it starts her transcription work. In this latest study, the researchers used high -power microscopes and advanced calculation methods to visually capture the enzyme and its auxiliary proteins.

The team has reconstructed the transcription process in a test tube, flash samples froze on microscopic grids and carefully imagined them from several angles with an electron microscope. This method, known as cryo-EM, can reveal the 3D structures of a protein in almost atomic details.

Karl Herbine, a graduate student who led the project (currently a postdoctoral scholarship holder at the University of Pennsylvania), has evaluated more than a million images in three years. The fruit of its perseverance is a molecular film which shows how the enzyme recognizes the correct starting point on DNA, brings auxiliary proteins, begins to copy the genetic code in mRNA and finally transitions into a fully active and stable mode.

With one in 5,000 people affected by mitochondrial disease, the results open the door to discover drugs designed to restore mitochondrial health.

“When we see how this fundamental process works,” says Dr. Temiakov, “we can start repairing what is broken.”