The findings, published April 9 in Human Molecular Genetics, could also have broader clinical implications for human metabolic diseases affecting other organ systems such as the liver and skeletal muscle.
“The heart is a muscle with high energy demands, so it’s no surprise that mitochondrial diseases are frequently accompanied by cardiac abnormalities. However, the molecular mechanisms involved in mitochondrial cardiomyopathy are not known,” said co-corresponding author Karen Ocorr, Ph.D., assistant professor in the Development, Aging, and Regeneration Program at Sanford-Burnham. “Our novel animal model provides new insight into this question and could pave the way for next-generation therapies not only for heart disease, but also potentially for non-alcoholic fatty liver disease and a wide range of metabolic disorders.”
Overcoming treatment challenges
Cardiomyopathy is associated with defects in an energy-producing cellular structure called the mitochondrion, also known as the powerhouse of the cell. This condition causes cardiac muscle to become weak and enlarged, making it difficult for the heart to pump enough blood to the rest of the body. Many patients are at risk for deadly heart arrhythmias and may need drugs or a defibrillator, while some develop severe heart failure and do not respond to medication, surgery, or other interventions.
Treatment options for mitochondrial cardiomyopathy have been limited in part by the lack of appropriate animal models. One challenge is that it is relatively difficult to manipulate genes in vertebrate models such as mice and rats. To overcome this hurdle, Ocorr, in collaboration with Rolf Bodmer, Ph.D., director of the Development, Aging, and Regeneration Program, has developed a novel methodology to study heart function in the fruit fly, or Drosophila, which is more amenable to genetic manipulation. “Since the genetic network controlling cardiac specification, differentiation, and function are conserved from flies to mammals, as well as many other aspects of heart function, Drosophila has become a powerful genetic model to study cardiomyopathies,” Ocorr said.
Unraveling energetic pathways
To study the molecular mechanisms of mitochondrial cardiomyopathy, Ocorr and Bodmer teamed up with lead study author Leticia Martínez-Morentin and senior study author Juan Arredondo of the Universidad Autónoma de Madrid. They focused on the role of SCO1 and SCO2 because these genes are strongly implicated in mitochondrial cardiomyopathy in humans. SCO proteins are known to play an important role in the assembly of cytochrome c oxidase (COX)—a mitochondrial protein that is critical for energy production in cells.
In the new study, the researchers developed the first animal model for human SCO-mediated cardiomyopathy. In a series of genetic experiments, they found that scox—the single fruit fly version of the mammalian SCO genes—is critical for normal heart function and structure. Reducing levels of the scox protein interfered with COX activity in heart muscle cells, shifting the balance of energy metabolism from oxidative phosphorylation to glycolysis.
This metabolic switch resulted in substantially less energy production in the cells, mimicking the clinical features found in patients with SCO mutations. Moreover, the metabolic stress signals activated a tumor suppressor gene called p53, which caused the heart muscle cells to undergo programmed cell death. As a result, flies lacking scox developed cardiomyopathy, showing a reduced heart rate and structural abnormalities as well as a shorter lifespan.
Spearheading the search for new drugs
In future studies, the researchers will search for other cellular components that interact with scox/SCO in an attempt to further characterize the newly discovered pathway by which it causes programmed cell death and cardiac dysfunction, with the goal of identifying additional targets for drug development. “p53 is involved in a lot of different cellular pathways, so if we can figure out the specific molecular connection between p53 and scox/SCO in causing cardiomyopathy we might come up with a druggable target that wouldn’t involve altering p53 function,” Ocorr explained.
Because SCO2 deficiency in mice also caused programmed cell death in the liver and skeletal muscle, the findings suggest that scox/SCO likely plays a similar role across species, including humans, and may underlie dysfunction in multiple organ systems. “Taken together, the findings greatly advance our understanding of the mechanisms and consequences involved in SCO deficiency and will likely have a significant impact on our understanding of a wide range of human metabolic diseases,” Ocorr said.
This post was written by Janelle Weaver, Ph.D., a freelance writer.
To read the paper in full, click here.