Long overlooked—or oversimplified—as primitive power plants in our cells, mitochondria are moving into the mainstream scientific limelight, thanks in large part to Douglas Wallace, PhD, the “world’s biggest mitochondriac” who is galvanizing research on the Penn and CHOP campuses into the role of cellular energy in disease.

By David Steen Martin | Photos by Peggy Peterson

If you doubt the importance of energy to human health, Douglas Wallace, PhD, suggests you consider a cadaver. It may be anatomically perfect. It is just dead. Why? It lacks energy.

Wallace, a professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania and director of the Center for Mitochondrial and Epigenomic Medicine at Children’s Hospital of Philadelphia (CHOP), has spent the last five decades pushing medicine to look beyond the body’s anatomy to focus on its energy.

“Western medicine is grounded in anatomy, which I call the anatomical paradigm of disease,” Wallace said. If you have severe headaches, you see a neurologist. “But what if the problem is systemic, and the head is just more sensitive to that systemic defect than any other organ? Treating the head will not solve the problem.”

Describing this conflict as “the conundrum created by mitochondrial disease,” Wallace has focused his career on tiny structures inside our cells called mitochondria. Mitochondria convert oxygen we breathe and nutrients in our food to generate 90 percent of the energy in the human body. Biology textbooks have traditionally depicted mitochondria as primitive bean-shaped organelles in cells—simple power plants, churning out energy, but of little relevance to medicine. But this conventional wisdom is misguided, according to Wallace’s pioneering research.

Wallace’s work has not only permitted him to reconstruct the prehistory of our species, but has demonstrated that mitochondrial energetics impinges on virtually every aspect of medicine. Consequently, Wallace and his colleagues within the Center for Mitochondrial and Epigenomic Medicine collaborate with physicians and scientists across the medical landscape, both within Penn and CHOP and around the world. These studies have demonstrated that mitochondria play a role in a wide spectrum of intractable diseases and conditions from autism, Parkinson’s and Alzheimer’s diseases to diabetes, obesity, and heart disease; as well as cancer and aging.

Ancient Bacteria

The story of how and why mitochondria came to be so crucial to our health begins two or three billion years ago, with a once-in-the-history-of-life event. This event was the formation of a symbiosis between two originally co-equal single-celled life forms, an oxidative bacterium that evolved into the mitochondria inside of all complex, non-bacterial cells, and an archaeon that would evolve to become the nucleus and everything else surrounding the mitochondria inside these cells. Without this singular episode in the history of life on Earth, there would be no plants, animals, or you.

Without the singular episode in the history of life on Earth when two single-celled life forms became complex cells that included mitochondria, there would be no plants, animals, or you.

The mitochondria brought to the partnership their unique ability to use newly abundant oxygen from the atmosphere to extract chemical energy from carbohydrates that were consumed as food. Once established in their cellular symbiosis, the mitochondria proliferated inside the larger cell and collectively produced sufficient excess energy for the nucleus to increase the number and complexity of its genes. The increased genes permitted increased complexity of life.

The strength of this symbiotic relationship, powered by energy and driving all life processes, has been likened to Prometheus’ mythical gift of fire.

“If mitochondria had not happened, nothing that you see out there would exist,” Wallace said, waving a hand toward the panoramic view from a sixth-floor window at CHOP.

Given how much we depend on mitochondria, we know remarkably little about them. Mitochondria weren’t even discovered until late in the 19th century. By the 1950s, scientists including Penn’s Britton Chance, PhD, were probing the physical and electrical properties of mitochondria to understand their role in powering cells. Chance, a fellow and later director of Penn’s Eldridge Reeves Johnson Foundation for Research in Medical Physics, was a pioneer in creating instruments to measure mitochondrial energetics. In a series of groundbreaking articles, six of them published in a single issue of the Journal of Biological Chemistry in 1955, Chance delineated the key aspects of how mitochondria produce energy, a process called oxidative phosphorylation (OXPHOS).

But it wasn’t until the 1960s that researchers found that the mitochondria had their own DNA (mtDNA), retained from their origins as an independent life form. Around this time, the idea that mitochondria originated as ancient bacteria began to gain wider credence in science.

Wallace arrived at Yale as a graduate student in 1970 intent on studying mitochondrial genetics in the medical school’s newly established department of Human Genetics. Though perceived as offbeat by those around him, Wallace’s mitochondrial pursuit fit with his lifelong quest to answer three questions: “Who am I? Where did I come from? And why do I feel bad?” Wallace reasoned that because the mitochondria generated 90 percent of cellular energy they couldn’t be trivial, and because the mitochondria had been recently found to have their own DNA, the mtDNA could mutate and cause disease. Moreover, the mtDNA was the only human DNA that could be purified at the time. So Wallace was able to begin studying human molecular genetics.  

Without the singular episode in the history of life on Earth when two single-celled life forms became complex cells that included mitochondria, there would have been no plants and no animals, trilobites or human beings.

We now know that mtDNA includes the genes required to assemble enzymes essential to the primary energy-generating process, OXPHOS. The mitochondria continue to function as distinct living organisms inside our cells, carrying out the process of copying their mtDNA within the mitochondrion and using those genes to build OXPHOS proteins using their own mitochondria-specific ribosomes. But this distinctness is balanced with dependence. While the ancient ancestors of mitochondria had DNA that encompassed all of the genes necessary for a free-living bacterium, following the symbiosis, mitochondria lost many genes they no longer needed in the protective intracellular environment. Mitochondria also outsourced their anatomical genes to the nucleus. The mtDNA retained only the most critical genes for OXPHOS charge conduction. Thus, the mtDNA is the wiring diagram of the mitochondrial power plant, and human energy now requires interaction between genes in mtDNA and the nuclear DNA (nDNA). Unlike nDNA, in which each cell carries only two copies (one inherited from each parent), mtDNA has thousands of copies in every cell.

As a graduate student, Wallace split his time between the lab, where he began to define the rules of mtDNA genetics, and conversations with biophysicist Harold Morowitz, exploring theories about the fundamental physics of life. From these early days and for decades to come, Wallace encountered a scientific establishment that thought his focus on mitochondria was misguided. One early supervisor said to Wallace, “Why are you wasting your career on mitochondria? Mitochondria have nothing to do with medicine.”

Uprooting the Pea Plant

The same biology textbooks that describe mitochondria as inert power plants typically introduce genetics with the story of the neat rules first set down by Augustinian monk Gregor Mendel in the mid-19th century. Mendel, the son of a struggling farmer, discovered the fundamental laws of genetics that govern inheritance of nDNA by studying pea plants in a small garden plot on his monastery’s grounds in what is now the Czech Republic. By cross-breeding his plants over multiple generations, Mendel showed that for several inherited traits each parent passed along one copy of each gene to their offspring.

Wallace’s research uprooted the notion that all genetics followed Mendel’s pea-plant ideal.

In the decades after he started working as a graduate student at Yale, Wallace’s research uprooted the notion that all genetics followed Mendel’s pea-plant ideal. Wallace not only described a completely different human genetic system, but went on to demonstrate that genetic defects in the mtDNA can play a fundamental role in disease (more on that below) and to show that ancient mtDNA variants permitted our ancestors to adapt to different environments to colonize the globe.

Though Mendel’s model describes ordinary inheritance patterns of nDNA well—one copy of each gene inherited from each parent—Wallace showed that mtDNA is solely inherited from the mother, passed on through her oocyte (egg) at fertilization. Each cell has hundreds to thousands of mtDNAs, and the oocyte contains several hundred thousand mtDNAs. This means that mutations in mtDNA affect a living organism in a different kind of pattern. While a nuclear gene mutation can exist in three states: two normal, one normal and one mutant, and two mutant copies, by contrast, a mtDNA mutation can be present in a vast gradient of different percentages of the cell’s mtDNA.

Wallace made an inductive leap from this insight to investigation and discoveries about human prehistory. Because the mtDNA is exclusively maternally inherited, it can only change over generations by the accumulation of sequential mutations along maternal lineages. Thus, the number of mtDNA sequence differences between any two individuals is proportional to the time since they shared a common female ancestor. By analyzing the mtDNA sequence differences between indigenous peoples from around the world, Wallace and associates determined the genetic relatedness of different people. By overlaying their genetic relationships with their geographic homeland, Wallace and colleagues were able to reconstruct the ancient origin and migration of peoples.

To do this work, Wallace and his team traveled around the globe getting samples of mtDNA. His favorite place was Siberia’s Lake Baikal, an ancient body of water in a vast plain that harbors 20 percent of the world’s fresh water. “It’s an ocean of absolutely pure, crystal clear water, and it’s thousands of feet deep,” Wallace recalled. “It has its own seals. Its own fish. It’s completely isolated.”

Using mitochondria to reconstruct human migrations led Wallace to conclude that all human mtDNAs diverged from a single mtDNA in Africa about 200,000 years ago, a mtDNA that has been christened “mitochondrial Eve.” After radiating in Africa for about 140,000 years, the descendants of only two mtDNA lineages left Africa about 65,000 years ago to colonize Eurasia. Of the numerous Eurasian mtDNA lineages, people from only five mtDNA lineages from Eurasia initially colonized the Americas.

The regional mtDNA lineages don’t only represent chance mutations in mtDNA that are accumulated and inherited through maternal lines. Evolution is an ongoing process of selection in favor of mutations that offer some benefit to survival in an environment, as well as selection against mutations that cause harm. The major human lineages of mtDNA generally diverged from one another with the appearance of a mtDNA harboring a functional variant. This implies that these founder variants were advantageous in the environment in which they arose, and these variants became enriched by selection.

For Wallace, these insights into human prehistory and evolution are intricately connected with insights into mitochondria’s role in health. Variations in mtDNA that were adaptive in one environment can be maladaptive in another environment. Consistent with this concept, mtDNA lineages have been found to be associated with a wide range of metabolic and degenerative diseases, longevity, and cancer. But mtDNA mutations are far more directly implicated in certain rare diseases today—also thanks to Wallace’s early insight.

Mitochondrial Medicine

The field of mitochondrial molecular medicine was founded in 1988 when Wallace and associates at Emory reported the first inherited pathogenic mtDNA mutation causing a hereditary disease, Leber Hereditary Optic Neuropathy (LHON). LHON is a form of acute-onset blindness that presents in the teens or twenties. Since this discovery, mutations in mtDNA have been linked to forms of deafness, neurodegeneration, stroke, seizures, dementia, heart disease, kidney problems, chronic fatigue, exercise intolerance, diabetes, gastrointestinal impairments, mood disorders, various cancers, and aging. Known inherited and acquired mitochondrial defects affect an estimated 1 in 4,300 people.

Mitochondrial genetic diseases today are increasingly recognized but clinically vexing. Like many rare diseases, they are often overlooked and misdiagnosed. Wallace’s first patient was a woman with a bump on her back called a cervical lipoma, in addition to progressive dementia, heart disease, and gastrointestinal problems. She was receiving psychiatric care because doctors could not envision that a patient could have symptoms in so many different organs due to the same cause. Wallace found she had a mtDNA mutation. He has since seen many others like her with constellations of symptoms affecting multiple organs.

At CHOP, the Mitochondrial Medicine Frontier Program is one of a handful of centers worldwide specializing in mitochondrial disease. The program focuses on finding the underlying cause of a condition and finding the best treatments available, integrating clinical care across the spectrum of disease, and bridging clinical care with clinical research to improve outcomes. Mitochondrial dysfunction can damage any organ in the body and affect individuals from conception to old age. 

“Patients typically have many symptoms progressively involving many organs,” said Marni Falk, MD, the program’s executive director, an associate professor of Pediatrics at the Perelman School of Medicine, and chair of the Scientific and Medical Advisory Board of the United Mitochondrial Disease Foundation. Falk was co-author of a consensus statement published in July in Genetics in Medicine on preventative guidelines for the management and care of people with mitochondrial disease. She also leads an active CHOP research group to gain better understanding of the causes, consequences, and novel therapeutic approaches for mitochondrial disease.

Current treatments are typically aimed at keeping these patients as healthy as possible through attentive clinical care, exercise, vitamins, and nutritional supplements, while avoiding medications known to be toxic to mitochondria. One actively discussed approach for eliminating harmful mtDNA mutations from being inherited in an embryo is a reproductive technique in which the nucleus from the oocyte or zygote of the mother is transferred into a donated egg from a woman with normal mtDNAs, from which the nucleus has been removed. A few such “three-parent babies” have been born, at least one of which had low levels of the harmful mtDNA; the controversial technique is one of the rare occasions when mitochondrial medical research has received popular attention. Recently, Falk served on a National Academy of Medicine panel weighing the ethical considerations of these techniques. In addition, gene therapy or stem cell therapy has potential to repair mutations in the mitochondria, and some pharmaceutical compounds are being studied that could promote mitochondrial health.

“There are a lot of therapies in the pipeline,” Falk said. “I’m very hopeful we’re going to reach the point where we have a series of approved therapies to choose from to target different manifestations and improve health across different subtypes of mitochondrial disease. I don’t think it’s a matter of ‘if.’ It’s a matter of ‘when.’”

But getting funding for mitochondrial research can be difficult, Wallace noted, even though understanding how to treat patients in rare mitochondrial diseases may lead to new approaches for treating a wide range of common diseases.  

“This is a new way of looking at the disease process,” he said. “It has huge implications.”

A better understanding of mitochondria, in Wallace’s view, will change the way medicine understands health and disease. Traditional diagnoses focus on ailing organs. Heart disease originates in the heart, kidney disease in the kidney, Alzheimer’s and Parkinson’s diseases in the brain, and so on. To look at the body through Wallace’s lens is to hold the opposite end of the binoculars. Numerous common diseases may be mitochondrial bioenergetic diseases with organ-specific symptoms. Heart disease can be an energy problem, not one due to an inherent problem in the structure of the heart.

Wallace and those who have joined him in the now burgeoning field of mitochondrial research, with their talk about “bioenergetics,” sound more akin to practitioners of Eastern philosophy, with its concept of “vital energy” or “Qi.” The term bioenergetics may have a mystical ring, but discoveries linking mitochondria, energy and disease are converging into an active area in science and coming fast.

Cardiovascular Institute ‘Player-Coach’ Focused on Mitochondria

Daniel P. Kelly, MD, the new director of the Penn Cardiovascular Institute, considers himself a player-coach, a researcher and team builder with ideas about the kind of collaboration that can crack some of medicine’s most difficult challenges.

Breaking down barriers between disciplines and also between basic science and clinical research can open the door to breakthroughs in heart disease, diabetes, and cancer, Kelly said.

At the core of his approach is a focus on the mitochondria and energy production. The heart uses a lot of energy. People with heart failure are often unable to supply the heart with enough to function properly.

“If we could make the mitochondria more healthy, we might have one form of treatment for the global health problem of heart failure and sudden death,” Kelly said.

Heart failure costs more than $30 billion in the U.S. alone and costs are projected to double over the next 20 years. Current treatments for heart failure aim to lower the energy needs of the heart, relieving some of the symptoms but often leaving patients with a poor quality of life. However, therapies aimed at improving cardiac mitochondrial energy transduction have not been developed.

Kelly’s interest in this area was sparked by a rare genetic mitochondrial disease in children that could cause heart failure. He began studying it in his earliest research training as a young physician at Washington University in St. Louis.

“I was still seeing patients and still taking some call at night,” Kelly said, recalling the long hours. “It was exhilarating but somewhat disorienting.” As he worked late into the night on his research, shoulder-to-shoulder with graduate students, his beeper would go off with concerns about a patient.

“You know it’s something you like doing if you find yourself spending a lot of hours doing it but don’t count the hours,” he said. “I learned that there is nothing quite like the thrill of discovery. Particularly if it could impact dread diseases of our time.”

Kelly and his colleagues found the mitochondria in these young hearts had a genetic defect affecting an enzyme needed to break down fatty acids, a fuel source for mitochondria to provide usable energy the heart. When the children became ill with common viral diseases, the stress and fasting often precipitated heart failure due to energy starvation. The results were published in the Proceedings of the National Academy of Sciences in 1987.

Kelly began wondering if these rare mitochondrial diseases might offer insights into more common forms of heart disease, and his career changed course.

He was the founding director of the Center for Cardiovascular Research at Washington University and later the founding director of the Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Florida. There, he built a team focused on metabolism with a focus on diabetes and obesity and its cardiovascular complications.

Kelly said he considered Penn’s concentration of talent focused on mitochondria, metabolism, and disease second to none worldwide, between Wallace at CHOP and Penn’s Mitchell A. Lazar, MD, PhD, and the Institute for Diabetes, Obesity and Metabolism. He officially joined them in his new role at Penn in August.

“From our passion in understanding mitochondria in disease, we take broader views beyond the heart, across disciplinary boundaries,” Kelly said. “This approach should lead to the assembly of ‘out of the box’ research teams across the Penn campus. Indeed, biomedical research is at a point where discoveries made by multidisciplinary groups are not only possible, but essential.”

“It All Goes Back to Britton Chance”

Among his many accomplishments, Britton Chance, PhD, was an Olympic gold medalist in sailing, a prolific
inventor, and a first describer of the process by which mitochondria produce cellular energy.

One afternoon this summer, J. Kevin Foskett, PhD, the Isaac Ott Professor of Physiology at Penn, was planning a week-long assay of 44,000 compounds, to see how they affect the flow of calcium ions to mitochondria in cancer cells. It’s the first step of what he’s hoping will be a cancer treatment that targets mitochondria.

Foskett has found mitochondria in cancer cells are addicted to calcium. Normal cells will slow down energy production when they don’t have enough calcium. Under the same conditions, cancer cells continue to reproduce via mitosis, even though the lack of calcium limits the cells’ ability to function.

“Cancer cells proceed into mitosis even though they’re in a bioenergetics crisis and at the end of mitosis they kind of explode. What they call a mitotic catastrophe,” Foskett said. Stopping the flow of calcium to the mitochondria could be a way to kill cancer cells while sparing normal cells.

Foskett’s work is just one example of many across the Penn and CHOP campuses. More than 250 investigators participate in the CHOP/Penn Mitochondria Research Affinity Group led since 2008 by Marni Falk. Much of the ongoing work centers on the brain because this organ exerts such a high demand for energy that mitochondrial dysfunction is often evident there. The brain is only 2 or 3 percent of our body weight but expends 20 percent of its energy. Failure to deliver enough energy—the result of mitochondrial mutations—can result in neuropsychiatric disorders, Wallace argues. For example, his team reported a mtDNA mutation in 1993 that predisposes to Alzheimer’s and Parkinson’s diseases, and in August this year, Wallace’s team reported that certain Eurasian mtDNA lineages are predisposed to autism spectrum disorders. 

Efforts at Penn to understand the role of mitochondria in the brain span a number of areas and biological mechanisms. Erika Holzbaur, PhD, the William Maul Measey Professor of Physiology, is researching what happens to damaged mitochondria, a process called mitophagy. Her research could result in a better understanding of neurodegenerative disease, leading to new treatments. And James Eberwine, PhD, the Elmer Holmes Bobst Professor of Systems Pharmacology and Translational Therapeutics, is focusing on how mitochondria affect neuron function. The Eberwine lab has already developed a way to isolate and sequence single mitochondria from human neuronal cells, discovering a far greater diversity in mtDNA in single cells than expected. Work in his lab could make it possible one day to create therapeutic mitochondria and offer new ways to treat mitochondrial disease.

After the brain, the next-biggest consumers of energy in the body are the heart and muscles. Daniel Kelly, MD, who joined Penn in August as director of Penn’s Cardiovascular Institute, is focused on energy and heart disease, seeking ways to improve mitochondria to restore cardiac energy in heart failure patients. (See sidebar.) Kelly said the concentration of researchers at Penn and CHOP focused on mitochondria and bioenergetics is second to none in the world.

Foskett sees all this research on mitochondria as an extension of work at Penn that began almost a century ago.

“It all goes back to Britton Chance,” he said.

Chance was an inventor and innovator and Olympic gold medalist in sailing whose wide-ranging research spanned 70 years. He spent much of that time on bioenergetics, including his pioneering work that described how mitochondria generate energy through OXPHOS. He was still receiving research grants into his 90s.

“He was unbelievably vibrant, riding his bicycle down Hamilton walk to his research lab in his mid-90s,” Falk said. “A fabulous person, brilliant scientist, dedicated educator, and inspiring role model.” After Chance died in 2010, researchers traveled to Penn from all over the world to take part in a two-day memorial symposium to honor him.

Mitochondria Entering the Mainstream?

Wallace arrived at Penn and CHOP the year Chance died, and he is leading the next generation of work here on mitochondria. In addition to the role of mitochondria in disease, Wallace has taken aim at no less than the aging process itself. It’s no accident the elderly often describe having a lack of energy, Wallace said. He argues that aging is the equivalent of a “metropolitan brownout” caused by mitochondria becoming weaker as mtDNA accumulates more mutations. The mutation rate of mtDNA is hundreds of times greater than that of nuclear DNA.

Wallace believes that accumulation of mutations in the mtDNA in our tissues with age progressively erodes mitochondrial bioenergetics and is the molecular basis of our aging clock. These accumulated mtDNA mutations may also exacerbate inherited partial mtDNA defects in mechanisms resulting in diseases with a delayed onset and progressive course.  

This idea hasn’t uprooted the mainstream understanding of aging yet, but Wallace is accustomed to challenging the status quo. For much of his career, the 70-year-old Wallace has worked in the face of naysayers who have considered his focus on mitochondria misguided and his findings irrelevant. “I’ve always been out in left field relative to the establishment,” Wallace said.

Lately, the establishment has been paying attention. In recognition of his groundbreaking work, Wallace this year received the Dr. Paul Janssen Award for Biomedical Research and a Benjamin Franklin Medal in Life Sciences. Previous recipients of the Franklin Medal include Albert Einstein, Thomas Edison, Stephen Hawking, Marie Curie, Nikola Tesla and Max Planck. More than 100 Franklin Medal winners have also won the Nobel Prize.

As a token of recently won accolades, Wallace likes to wear a small, gold pin on the lapel of his sport coat. He received the medallion for winning the 2012 Gruber Prize for Genetics, the world’s highest prize for genetics.

“I wear it because I have taken so much grief for trying to change the genetic paradigm,” Wallace said.

As someone who describes himself as “the world’s biggest mitochondriac,” Wallace said he is heartened by the increasing attention mitochondria are receiving. A look at scientific literature since 1980 found a steep rise in papers focused on mitochondria. In fact, they now outnumber papers on the human genome

As researchers look closer, they are finding mitochondria play a bigger role than previously thought possible. No longer dismissing them as static power plants, researchers have found mitochondria are able to move from one cell to another, and communicate within and across cells. Mitochondrial signaling is involved in the body’s response to inflammation and viruses. One analysis by Wallace’s research group even found mitochondria have the ability to regulate the expression of a large proportion of the genes in the human genome.

What might the testing and treatment for diseases look like in the future if doctors took a bioenergetics-focused approach instead of an organ-centric view? Find out on the Penn Medicine News Blog.

In defiance of his early supervisor’s assumption that mitochondria were medically irrelevant, Wallace predicts research will find mitochondria play an ever larger role in health, eventually leading doctors to put energy and anatomy on equal footing. Once considered irrelevant himself, Wallace now sees a vanguard of mitochondria researchers reshaping medicine.

“We’re going to change the way medicine is organized,” Wallace said.

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