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A mitochondrial etiology of metabolic and degenerative diseases, cancer and aging

Wednesday, April 2, 2014


Douglas C. Wallace, Ph.D.
Director, Center for Mitochondrial and Epigenomic Medicine (CMEM)
Professor, Department of Pathology & Laboratory Medicine
The Children’s Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania

More than 35 years ago, Dr. Wallace and his colleagues founded the field of human mitochondrial genetics. The mitochondria are the cellular power plants, organelles that generate most of the cell’s energy. The mitochondria also contain their own DNA, the mitochondrial DNA (mtDNA), which encodes the wiring diagram for the cell’s power plants. Dr. Wallace showed that the mtDNA is inherited exclusively from the mother and that genetic alterations in the mtDNA can result is a wide range of metabolic and degenerative diseases as well as being important in cancer and aging.

One of Dr. Wallace’s seminal contributions has been to use mtDNA variation to reconstruct the origin and ancient migrations of women. These studies 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 to populate the Americas. Studies on the paternally inherited Y chromosome showed that men went along too.


For half a millennium Western medicine has focused on anatomy and for the past century on nuclear DNA (nDNA), Mendelian, genetics. While these concepts have permitted many biomedical advances, they have proven insufficient for understanding the common “complex” diseases. Life requires energy, 90 percent of which comes from the mitochondrion. The mitochondrial genome consists of thousands of copies of the maternally inherited mitochondrial DNA (mtDNA) plus 1,000–2,000 nDNA genes. The mtDNA has a very high mutation rate, but the most deleterious mutations are removed by an ovarian prefertilization selection system. Hence, functional mtDNA variants are constantly being introduced into the human population, the more deleterious resulting in recent maternally inherited diseases. The milder mtDNA variants have accumulated sequentially as women spread throughout Africa and migrated out to colonize Eurasia and the Americas. Some ancient mtDNA variants alter mitochondrial energy metabolism in ways that were beneficial in different regional environments. In alternative environments and/or with age these same adaptive variants can be maladaptive and increase the risk for disease. For example, one variant increases the penetrance of mutations associated with an inherited form of vision loss, but is adaptive for survival at high altitudes, such as in the Tibetans. Mutations in the mtDNAs also accumulate with age in both stem and somatic tissue cells and can be associated with various forms of cancer. The introduction of mtDNA variants into the mouse germline via female embryonic stem cells has confirmed the causal role of mitochondrial deficiency in diseases. Hence, the pathophysiology of some common diseases may be bioenergetic dysfunction and their genetic complexity the result of thousands of nDNA and mtDNA bioenergetic gene variants interacting.

The page was last updated on Thursday, April 2, 2015 - 4:10pm