April 22, 2014
Mitochondrial Repair May Be Culprit Behind Muscle Weakness In Mitochondrial Diseases, Alcoholics
April Flowers for redOrbit.com - Your Universe Online
Long-time alcoholics and patients with mitochondrial disease both suffer with muscle weakness, but it wasn't until a new study from Thomas Jefferson University that a common link was found. According to the findings, described in The Journal of Cell Biology, the link involves mitochondria that are unable to self-repair. This information gives researchers a new method for diagnosing mitochondrial disease, as well as a target for new drug therapies.When mitochondria are damaged, they fuse with other, healthy mitochondria and exchange contents. The damaged parts are segregated for recycling, and properly functioning proteins are donated from healthy mitochondria to replace them. Mitochondria are necessary for the body because they are organelles that produce the energy needed for muscle, brain, and every other cell type in the body.
Scientists have known that fusion is a major method for mitochondrial repair for many types of cells in the body, but they have been puzzled over the method for repair in skeletal muscle. Because skeletal muscle relies on mitochondria for constant power, this makes repair a frequent necessity. Most researchers, however, have assumed that fusion was impossible because the mitochondria in this type of cell are squeezed so tightly in between the packed fibers of the muscle cells.
Research into two mitochondrial diseases — Autosomal Dominant Optical Atropy (ADOA) disease and a type of Charcot-Marie-Tooth (CMT) disease — led to the idea that fusion might be crucial for normal muscle function. Both diseases share a symptom — muscle weakness — and a mutation in one of the three genes that are involved in mitochondrial fusion.
For the new study, Veronica Eisner, Ph.D., a postdoctoral fellow at Thomas Jefferson University, worked with Dr. Gyorgy Hajnoczky, M.D., Ph.D., Director of Jefferson's MitoCare Center and professor in the department of Pathology, Anatomy & Cell Biology, and a team of researchers. Eisner developed a system to tag the mitochondria in the skeletal muscle cells of rats with two different colors to determine whether mitochondria in the muscle could indeed fuse to regenerate. She then watched to see if the colors mingled. The system started with Eisner genetically engineering a rat model whose mitochondria expressed the color red at all times. She also engineered the mitochondria in the cells to turn green when zapped with a laser, which would create squares of green-shining mitochondria within the steady red background. Eisner was surprised to see the green mitochondria mingling with the red and exchanging contents, as well as traveling to other areas where only red-colored mitochondria had existed before. Eisner said the results were exciting because they revealed "for the first time that mitochondrial fusion occurs in muscle cells."
The team determined that of the mitofusin (Mfn) fusion proteins, Mfn1 was most important in skeletal muscle cells, which allowed them to begin testing whether mitochondrial fusion was the culprit in other examples of muscle weakness, such as alcoholism. Mfn1 abundance decreased by as much as 50 percent in rats on a regular diet of alcohol. Other fusion proteins, however, were unchanged. The Mfn1 decrease occurred simultaneously with a massive decrease in mitochondrial fusion. Fusion was restored at the same time as Mfn1 abundance. These shifts were linked with increased muscle fatigue, as well.
"That alcohol can have a specific effect on this one gene involved in mitochondrial fusion suggests that other environmental factors may also specifically alter mitochondrial fusion and repair," says Dr. Hajnoczky.
"The work provides more evidence to support the concept that fission and fusion -- or mitochondrial dynamics -- may be responsible for more than just a subset of mitochondrial diseases we know of," says Dr. Hajnoczky. "In addition, knowing the proteins involved in the process gives us the possibility of developing a drug."