Credit: Peggy Peterson
What could medicine look like someday if, instead of focusing primarily on the organ affected by a disease — neurologists examining brain diseases, pulmonologists focusing on lung diseases — our system was centered on how cells process energy?
If this sounds like an arcane or weird question to pose as a “what if” scenario, you probably haven’t spent much time lately thinking about mitochondria. And you’re not alone. In the day-to-day treatment of most illnesses today, physicians typically don’t need to even to draw on the basic knowledge about mitochondria that some of us might recall from high school biology: Mitochondria are the jellybean-shaped organelles inside of cells that act as the power plants providing most of the energy our bodies need.
But among the small number of scientists and physicians who do study mitochondria, there’s emerging support for a fairly radical idea that the energetic functioning of these power plants might be a crucial and underappreciated component of health and disease.
Today, it’s pretty obvious that if you have severe headaches, a neurologist is the person best equipped to help you. “But what if the problem is systemic, and the head is just more sensitive to that systemic defect than any other organ?” a leading mitochondrial expert asks in the new issue of Penn Medicine magazine. “Treating the head will not solve the problem.”
That expert, Douglas Wallace, PhD, a professor of Pathology and Laboratory Medicine at Penn and director of the Center for Mitochondrial and Epigenomic Medicine at Children’s Hospital of Philadelphia, describes himself as “the world’s most extreme mitochondriac.” As the Penn Medicine magazine story tells, for much of his career, Wallace’s ideas about the importance of mitochondria and their bioenergetic functioning in health and disease that originated outside the mainstream of medical thought have gained increasing acceptance as he has racked up evidence, piece by piece. This year, he was awarded the prestigious Franklin Medal in Life Science and the Dr. Paul Janssen Award for Biomedical Research.
Imaging of individual blood cells by Jang and Eckmann shows that mitochondria (shown as dots) are less likely to be found near the cell’s periphery in patients with sepsis (image A) than in a healthy person (image B). The red and blue coloring indicates degree of movement; mitochondria in sepsis patients’ cells move less in comparison to mitochondria in a healthy person’s cells.
These recent accolades may signal a growing understanding that his ideas about bioenergetics could be more broadly applicable to many different diseases that affect those of us whose mitochondria work well enough that, currently, our doctors don’t need
to think about them. (Typically, when mitochondria come up in medical care today, it’s in the context of extremely rare and complex genetic diseases that are most often identified in childhood.) Wallace and other “mitochondriacs” contend that mitochondria are crucial to numerous disease states, including neuropsychiatric and cardiac conditions, even diabetes — and as evidence accumulates in support of that contention, medicine might need to change.
So we return to our “what if” scenario: If this idea is correct, what might bioenergetics-focused medicine look like?
We can begin to glimpse some answers to that question with a visit to a basement lab just steps away from the hyperbaric chamber where patients at the Hospital of the University of Pennsylvania receive treatment for carbon monoxide poisoning. Working here, two Penn physicians and their team think mitochondria might provide a valuable biomarker to indicate how well the oxygenation therapy provided in these chambers is helping.
“Unfortunately, there just isn’t a very good prognostic marker of how sick these patients are or how ultimately they will do,” said David Jang, MD, an assistant professor of Emergency Medicine who has a particular interest in toxicology.
“Some of those patients go into hyperbaric therapy and they come out later looking nice and pink and their blood numbers for oxygenation look pristine, until they then have a seizure or a cardiac event,” added David Eckmann, MD, PhD, a professor of Anesthesiology and Bioengineering. “We obviously don't have the right end point, and it's obviously not the complete therapy.”
Instead, they want to develop a blood test to rapidly assess how well the body is truly processing oxygen via the mitochondria. They published results from a preliminary pilot study of one such method using patient blood cells in the journal Clinical Toxicology in July. Their pilot study showed the test of mitochondrial functioning could be conducted quickly enough to be clinically useful. They also found preliminary indications that mitochondrial respiration might correlate better with patients’ outcomes than the level of carbon monoxide in the blood. They are now pursuing larger studies and similar studies with sepsis, a severe form of infection that is the leading cause of patient deaths in intensive-care settings.
Credit: Graham Perry
In addition to measuring the chemical or energetic output from mitochondria, Eckmann and Jang also think that they might detect how well mitochondria are working just by looking at them. They recently partnered with a team of Israeli researchers to study cells from patients with a severe neurological disease — in this case, fibroblasts, not nerve cells — to use a visualization algorithm see how mitochondrial movement and positioning might differ in comparison to cells from healthy individuals. “In the diseased cells, those cells coming from the patient samples, mitochondrial motility was considerably depressed,” Eckmann said. “There's also just a complete difference in the partitioning. In the normal cells, you see lots of mitochondria out in the periphery of those cells. In the diseased cells, they are all basically clustered around the nucleus.” That positioning indicates that the cells can’t process energy at their periphery — a bioenergetic dysfunction underlying a disease with neurological symptoms. The results were published in the journal Brain
“Hopefully in the near future we could take samples from a wide variety of pathological diseases, such as heart disease, cancer, and poisoning, and look at how mitochondria are working, not only how they consume oxygen but also how they are moving within the cell,” Jang said. “That could shed more light in terms of pathology, as well as therapeutics.”
To work toward developing future bioenergetics-focused therapies, they can begin with an existing part of their assessments of how well mitochondria are working. In this process, they systematically disrupt each of several distinct steps in the process by which mitochondria consume oxygen and create energy for the cell. In unhealthy mitochondria, this gives an indication of which specific steps are in need of repair. If drugs that help skip past the broken steps can be successfully delivered directly into the mitochondria — something Eckmann and Jang, among others, are attempting with a type of drugs called prodrugs — then someday a whole new class of therapies might be possible to treat bioenergetics aspects of disease, wherever they might manifest in the body.
“We're hopeful that, alongside the testing we develop, those who are on the pharma side of things will develop new types of therapies and they'll go hand in hand,” Eckmann said. “If we have a bedside or laboratory test to identify a patient’s bioenergetic defect, and then you have a library of things that will treat those different bioenergetic defects, that's where we'd like to be. Is that around the corner? No. Is that in my lifetime? I sure hope so.”