MitoSENS: Preventing Damage from Mitochondrial Mutations
Mitochondria are the “power plants” of your body’s cells. Mitochondria convert the nutrition inside your food into ATP, a type of energy that powers the biochemical reactions occurring in each of your cells. In a way, an individual mitochondrion is like a municipal power plant that serves a small city. Mitochondria turn resources into power the cell uses to function.
Cells are a bit like cities too, in that cells come equipped with DNA that tells various parts of the cell how to act – a bit similar to city planning concerned with the layout and design of the land. Various structures inside the cell read DNA like a set of instructions on how to do their jobs. A body cell keeps most of its DNA safely tucked away in its nucleus.
Mitochondria are different in that they have their own DNA, known as mtDNA, that they use as an instruction booklet to make the proteins that make up the machinery they use to harvest energy from our food and convert it to ATP. Mitochondria are also different from other cell structures because they keep this mtDNA nearby instead of storing the set of instructions in remote location inside the nucleus.
Just like municipal power plants, mitochondria create toxic waste as a byproduct. This toxic waste can pollute the surrounding cellular community and cause damage to structures within the cell. Mitochondria power plants spew out free radicals that impart particular damage to cellular structures.
Because of proximity to the power plant, mtDNA is at special risk for exposure to toxic waste. Free radicals can assault vulnerable mtDNA and delete large chunks of genetic code. This can render the mitochondria incapable of reading the instructions for making the critical components these little power stations need to create energy.
To make matters worse, cells tend to hang on to mutant mitochondria while destroying healthy ones. As a result, once even one mitochondrion with these large deletions appears, its progeny quickly take over a healthy cell.
When mitochondria lack the ability to create power using their main energy-producing system, they fall into an abnormal metabolic state where they produce very little energy but generate large amounts of metabolic byproducts. Our cells are not equipped to handle great volumes of these byproducts, and are forced to export it.
Negative effects can spread from a handful of affected cells to the rest of the body as they export the metabolic byproducts produced by their mutant mitochondria, causing oxidative stress throughout the entire body.
The Solution
In a perfect world, scientists would simply prevent deletions in mitochondrial DNA or repair deletions before they cause harm. Unfortunately, science is nowhere near ready to prevent or repair mtDNA deletions. For now, the most reasonable approach is to engineer a system that protects cells from damage caused by mutant mitochondria.
One way of doing this is to create backup copies of mtDNA and safely tuck them away in the cell’s nucleus, where free radicals cannot harm the information contained within the mitochondrial genes. These backup copies can serve as instruction manuals in case free radicals delete the original genes lying close to the mitochondrial power plants. These backup genes allow the cell’s power plants to continue working normally and avoid turning into mutant mitochondria.
This approach of making backup copies is not new – evolution has already moved thousands of genes that were originally part of the mtDNA into the protective confines of the nucleus. Today, the mtDNA that mitochondria keep near the power plant contains instructions to build only the 13 different proteins it needs on a day-to-day basis, even though it originally contained over a thousand. The others are now safely ensconced in the nucleus.
Over the course of thousands of years, evolutionary forces moved the rest of the mitochondrial genetic code to the nucleus to keep the genes safe. When accessed, these genes create proteins in the main body of the cell, outside the mitochondria. The cell then imports the newly created proteins into the mitochondria through specialized transport docks in the mitochondria membranes.
The greatest challenge to importing the 13 remaining proteins is that they tend to fold up on themselves while in the main body of the cell, creating folded structures too large to fit through the transport docks.
One solution is to look at how other organisms may have overcome this problem. Evolution seems to favor modified genes that resist snarling in the cell body, so the answer may lie in adopting such tricks from other species.
Another solution might be to create molecular “braces” that prevent proteins from collapsing in the cell body long enough to pass through the narrow transport dock in the mitochondrial membrane.
Scientists at the SENS Research Foundation Research Center are working on a third approach: ways to allow decoding the “working copies” of backup copies of genes whose proteins are destined for the mitochondria to occur near mitochondria rather than far away in the cell body. Because they do not have so far to travel, proteins may pass through transport docks before they fold up.
This new approach was pioneered by Professor Marisol Corral-Debrinski at the Institut de la Vision at Pierre and Marie Curie University, Paris. SENS Research Foundation funding helped Dr. Corral-Debrinski’s team introduce into the eyes of a rat a mutated mitochondrial gene associated with an inherited form of blindness to cause vision loss in the lab animal. Using the same technique, the team then restored the rat’s vision.
The metabolic wastes of shuttered mitochondrial power plants pose real health hazards to all human body cells. SENS Research Foundation continues to work towards keeping mitochondria running and preventing the damage associated with this hazardous cellular waste.
