Mitochondria studies critical to search for heart failure cure

Randy Carnell/UW Medicine
Dr. Rong Tian (rignt) goes over data in a mitochondrial research lab with UW Medicine biochemistry graduate student Arianne Caudal.

The power of mitochondrial science has the potential to unlock new solutions for heart failure, according to a working group co-chaired by researchers at the University of Washington School of Medicine and Boston University School of Medicine and convened by the National Heart Lung and Blood Institute at the National Institutes of Health. This common chronic condition, in which the heart can’t pump or can’t fill adequately, causes weakness and shortness of breath, and diminishes life expectancy.

Few new therapies for heart failure have appeared over the past two decades. The urgency to find better options is intensifying. As survival rates from heart attacks have risen, more people who have suffered cardiac muscle damage are slipping into difficult-to-treat heart failure.

Dr. Wilson Colucci, chief of cardiovascular medicine at Boston University School of Medicine, co-chaired the mitochondria and heart failure NHLBI working group.

There are several new ideas, based on an array of the latest science findings, for getting out of that slump. The NHLBI’s latest report points out that science has, in recent years, discovered that the mitochondria in our cells have many unexpected functions, several of which contribute to heart health and disease.

For a long time, mitochondria were viewed only as the energy suppliers of cells. Now, newer evidence suggests that they have far higher executive roles, such as sensing and reacting to changes in the cellular environment, the report says. Mitochondria, they explain, oversee critical decision points in cell.

“Mitochondria are actually major controllers of the cell. They communicate with every part of the cell and coordinate cell survival and death decisions. That’s why mitochondria are now considered an important target for therapy,” said one of the heads of the NHLBI working group, Dr. Rong Tian. She is a physician-scientist and anesthesiology professor who directs the Mitochondria and Metabolism Center at the UW School of Medicine in Seattle.

“Leveraging substantial progress made in understanding how mitochondria respond can inform our implementation strategies to improve cardiovascular health,” the group’s report noted.

The NHLBI working group suggests that expanding this growing knowledge into clinical applications could improve the outlook for the prevention, assessment and treatment of heart failure. Their recommendations are published today, Oct. 1, in the American Heart Association medical journal, Circulation. Here is the report.

Their workshop was called, “Unlocking the Secrets of Mitochondria in the Cardiovascular System: Path to a Cure in Heart Failure.”

The working group consisted of 28 scientific and clinical representatives from many major medical universities and medical centers across the United States. In addition to Tian, other leaders of the this effort were cardiologist Dr. Wilson “Bill” S. Colucci, chief of Cardiovascular Medicine and the Thomas J. Ryan Professor of Medicine at the Boston University School of Medicine, and Dr. Lisa Schwartz Longacre, program director, Heart Failure Arrhythmias Branch at the NHLBI..

Current studies are revealing the roles of mitochondria in the origin and progression of heart failure and cardiac disease. Yet there is still an unmet need, the group wrote, to translate this basic research into mitochondrial-based therapy. Scientists, clinicians, engineers and other experts, the report suggests, would also need to work together to design critical new tools to measure and modify mitochondrial function in lab dishes and in living models, and from there to patient trials.

“We have some beautiful studies, the community collectively, that show we could fix the mitochondria in cell culture dish or small animal models, but there has been, for example, no drug available on the market to treat mitochondria in human diseases so that will be one of our focuses for a next step,” Tian said.

The working group outlined the top gaps in knowledge and methods that could be priorities for upcoming research:

  • Examining the many functions of mitochondria, how these biological roles are integrated, and identifying therapeutic targets based on the identification of these linked processes, particularly in the areas of oxidative metabolism and of inflammation.
  • Studying communication among cells’ mitochondria and with other parts of the cell, such as the nucleus (the central control tower for the cell) and cross-talk of mitochondria from different cells and tissues. Researchers especially want to listen in on signals issued in times of environmental stress. New biomarkers and ideas for intervening against disease mechanisms are a hoped-for outcome of such studies.
  • Identifying opportunities for precision medicine by looking at the effects of sex, genetic background, diet and environmental stresses on mitochondrial function, by better understanding the DNAs inside mitochondria, and by analyzing the interactions between cells’ nuclear and mitochondrial genomes.
  • Creating new imaging, analytical, and chemical tools for investigating and manipulating mitochondria function, including finding ways to deliver cargo into mitochondria.
  • Evaluating the potential benefit of mitochondrial-based therapies in patients with heart failure, and developing assays and biomarkers to determine which patients are most likely to benefit from a particular therapy, as well as standardizing protocols to measure the effectiveness of the therapy on mitochondrial function.

“Emerging therapies that can act to correct or modify the function of mitochondria hold tremendous promise in the treatment of heart failure. Our challenge now is to develop methods to assess mitochondrial function in humans so that we can identify the best candidates for this form of therapy and assess how well it is working,” Colucci said.

Among the groups’ overall recommendations for meeting these priorities would be: designing multidisciplinary and systems-based approaches to studying the role of mitochondria in health and disease and to discovering new therapies, sharing new tools for research among labs and institutions, and fostering more efficient ways to translate promising findings and interventions into patient trials.

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