Mitochondrial Pore: A Potential Game-Changer for Muscular Dystrophy Treatment

Mitochondria, the powerhouse of the cell helps prevent the muscle-wasting symptoms of muscular dystrophy (MD). The findings of the study are led by scientists at Cincinnati Children’s and published in Science Advances ().

“We have isolated the primary disease-causing component of muscular dystrophy to the mitochondrial permeability pore,” says the study’s corresponding author Jeffery Molkentin, PhD. “If we prevent this pore from functioning, dystrophic disease in the mouse models we studied almost completely vanishes. We see the protection lasting past one year of life in the mouse, which translates to about 40 years of life for a human.”

Muscular Dystrophy
Overview about muscular dystrophy, a muscle disease characterized by muscle weakness and muscle wasting.

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Molkentin is a widely respected expert in the basic science of muscle cell function and formation. He is co-executive director of the Heart Institute at Cincinnati Children’s and director of its Division of Cardiovascular Biology. He has studied muscular dystrophies for over 20 years.

Mice Genetics Sheds Light on Mitochondrial Pore's Role in Muscular Dystrophy

Molkentin cautions that this discovery was achieved by observing outcomes in mice that were genetically modified to lack two genes that control mitochondrial permeability transition pore (MPTP) formation. Much more research beyond this early success will be needed to develop a safe and effective treatment for people with MDs.

Mitochondria organelles are surrounded by their own membrane. However, when exposed to oxidative stress or a pathologic overload of calcium ions (Ca2+) mitochondria open a pore in their protective membrane. The influx of excess calcium causes the organelle to burst, which in turn causes muscle fibers to die, eventually leading to wasting of entire muscle groups.

This process of mitochondrial pore-regulated cell death has been observed in other conditions including heart muscle damage after heart attacks and neurodegenerative diseases including Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).

Myotonic Dystrophy
Detailed information on myotonic muscular dystrophy, a common form of muscular disease that affects adults and children.

In this study, Molkentin and colleagues reveal the mechanisms at work when this mitochondria-destroying process occurs in MDs. The team determined that two genes in mice—Slc25a4 and Ppif—work in concert to mediate unwanted pore formation. Controlling either one by themselves only slowed MD progression, but the absence of both together stopped it.

“We found direct evidence that these genes produce required components that govern cell death, which opens a previously unrecognized pathway for potentially treating MDs and other necrotic diseases,” Molkentin says.

Quiz on Muscular Dystrophy
Muscular dystrophy is a condition that affects muscles and sometimes severely disables the patient. Duchenne muscular dystrophy is the most common type of muscular dystrophy. Would you like to test your knowledge on this particular disease? Here is ...

Developing a medication to protect mitochondria in muscle cells will require much more study, Molkentin says.

Exploring the Potential of the Mouse Gene Ppif and CypD Protein in Muscular Dystrophy

The mouse gene Ppif produces a protein called CypD. Researchers established years ago that the immune-suppressing drug cyclosporin A can block this protein, but long-term use of the drug at high doses poses significant risk of side effects. In MD, the drug only mildly slows the disease in animal models.

Meanwhile, the mouse gene Slc25a4 encodes a protein called ANT1. There are no medications that target this protein. The existing compounds known to bind with this protein are fatally toxic, so new compounds would be needed.

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“If a nontoxic ANT inhibitor can be identified, that also can target the mitochondrial pore, our results suggest that combined treatment with low dosages of a CypD inhibitor could be a novel therapeutic strategy,” Molkentin says. “Such a treatment could provide benefits independently or in combination with other gene therapies.”

Would such a treatment “cure” muscular dystrophy? It’s too soon to say. This study focused exclusively on skeletal muscle. More research would be needed to determine if the mitochondria-protecting approach also would protect against MD-related heart damage or other organ dysfunctions.

Reference:

ANT-dependent MPTP underlies necrotic myofiber death in muscular dystrophy - (https://www.science.org/doi/10.1126/sciadv.adi2767)

Source-Eurekalert