Understanding Mitochondria: A Shifting Paradigm for How Diseases are Treated and Prevented
The mitochondrion is the cellular power plant and a key supplier of the energy needed for the multiple functions of our cells such as metabolism, signaling, growth, reproduction, and even death. These organelles, of which there are hundreds in each cell, play a pivotal role in human health and disease.
Mitochondria contain their own DNA, called the mitochondrial DNA (mtDNA). While the DNA in a cell’s nucleus encodes the structure of both the cell and the mitochondria, the mtDNA encodes the wiring diagram for the cellular power plants.
As is the case in a metropolitan brown out, when the mitochondrial power plants of our cells become damaged the energy output for the body’s cells and tissues progressively declines. And since certain tissues have higher energy demands than others, one organ after another begins to malfunction as that critical mitochondrial energy decreases. The organs with the highest requirement for mitochondrial energy are those in the central nervous and endocrine systems, and the heart, muscle, and kidneys – the same organs that are most commonly affected in diseases and aging.
The realization that systemic energy defects can lead to organ-specific symptoms provides a striking alternative to the traditional Western medical perspective that organ-specific symptoms are due to organ-specific defects. Determining the inner workings of the mitochondria therefore promises to provide a major new approach to understanding and developing therapies for myriad rare and common diseases in children and adults.
The mitochondrion is a powerhouse, indeed.
Investigators are starting to take a closer look at the mitochondrion and its energy, and Children’s Hospital is leading this unique field of study that could one day shift our most fundamental biomedical paradigms.
The role of mitochondrial energy in human health and disease has long been the investigative focus of Douglas Wallace, PhD. In 2010, he moved his pioneering, world-renowned research program to The Children’s Hospital of Philadelphia Research Institute to join the already vibrant group of physicians and scientists at the Hospital and the University of Pennsylvania who are pursuing the highly promising new field of mitochondrial medicine.
More than 35 years ago, Dr. Wallace and his colleagues founded the field of human mitochondrial genetics by demonstrating that the human mitochondria encode genetic traits that are separate from those of the nucleus. He subsequently linked these traits to the mtDNA and demonstrated that the genetic rules of the mtDNA are very different from those of the nuclear DNA. The mtDNA is inherited exclusively from the mother and is present in thousands of copies per cell, unlike the traditional two copies of each gene in the nuclear DNA, so cells can have different percentages of damaged and normal mtDNA.
Knowledge of these novel genetic rules and the realization that the mtDNA encodes the central energy genes has permitted a growing number of biomedical scientists around the world to link mitochondrial dysfunction to a wide range of metabolic and degenerative diseases as well as cancer and aging.
Demonstration of the exclusive maternal inheritance of the mtDNA also permitted Dr. Wallace and his colleagues to reconstruct the origin and ancient migrations of women based on the realization that the number of mutational differences between two individuals is directly proportional to the time since they shared a common mother. These seminal studies have revealed that humans arose in Africa approximately 200,000 years ago; that women left Africa about 65,000 years ago to colonize Eurasia; and from Siberia, they crossed the Bering land bridge starting around 20,000 years ago to populate the Americas.
Dr. Wallace continues his groundbreaking research at Children’s Hospital as the Michael and Charles Barnett Chair in Pediatric Mitochondrial Medicine and Metabolic Diseases and directs a new Center of Emphasis at CHOP Research – the Center for Mitochondrial and Epigenomic Medicine.
By shifting the medical perspective from the anatomy of disease and nuclear genetics to the energetics of disease and non-nuclear genetics, Dr. Wallace and his team are providing a mechanistic understanding of holistic medicine. This is providing a bridge between the medical traditions of the West and East.
“Because energy flow is central to all life processes, mitochondria play a central role throughout the life cycle,” says Dr. Wallace, the first CHOP Research investigator who is a member in the prestigious National Academy of Sciences. “Therefore, our findings in age-related diseases help us to better understand how mitochondria dysfunction contributes to pediatric diseases, and vice-versa.”
He adds that the potential is great for contributing knowledge of mitochondrial medicine to the innovative clinical and research programs at Children’s Hospital and the University of Pennsylvania.
“These institutions have numerous outstanding physicians and scientists, and a strong tradition of interest in mitochondrial energy production through the leadership of Professor Britton Chance,” notes Dr. Wallace. “If we are successful in bringing the clinical and mitochondrial communities together, CHOP and Penn will be at the epicenter for an exciting new way to look at the disease processes, which promises to restructure medical thinking and lead to the prevention and treatment of a broad spectrum of human illnesses.”
