Mitochondria Study Offers Insights into Diseases' Underlying Causes

Recent work by a mitochondrial medicine pioneer from The Children’s Hospital of Philadelphia details how subtle changes in mitochondrial function may cause a broad range of common metabolic and degenerative diseases. Mitochondria are tiny energy-producing structures within our cells that contain their own DNA. The research offers “key insights into understanding the underlying cause of metabolic and neurodegenerative disorders such as diabetes, Alzheimer, Parkinson and Huntington disease, as well as human aging,” said CHOP Research’s Douglas C. Wallace, PhD.

The new research, published in the Proceedings of the National Academy of Sciences (PNAS), shows that small changes in the ratio of mutant to normal mitochondrial DNA within the thousands of mitochondrial DNAs inside each cell can cause abrupt changes in the expression of numerous genes within the nuclear DNA. Furthermore, the different proportions of mutant mitochondrial DNA that result in altered nuclear gene expression correspond to the same proportions of mutations in mitochondrial DNA that are associated with diabetes and autism; brain, heart, and muscle disease; or lethal infantile disease.

“By showing that subtle changes in the cellular proportion of the same mitochondrial DNA mutation can result in a wide range of different clinical manifestations, these findings challenge the traditional model that a single mutation causes a single disease,” said Dr. Wallace, director of the Center for Mitochondrial and Epigenomic Medicine and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania.

Existing in hundreds or thousands of copies outside the nucleus of every cell, mitochondria have their own DNA, distinct from the well-known DNA inside the cell nucleus. Although mitochondrial DNA (mtDNA) holds far fewer genes than nuclear DNA, mtDNA exchanges signals with nuclear DNA and participates in complicated networks of biochemical reactions essential to life.

The PNAS study builds on Dr. Wallace’s more than 40 years of investigating the mysteries of mitochondria. And it reinforces the argument he has presented over the course of his career: that mitochondria play a central, largely under-recognized role in all common human diseases. He has long argued that a traditional biomedical approach focusing on anatomy and individual organs does not provide the insights generated from a systems biology, bioenergetics-focused approach.

Examining Mitochondrial Mutations’ Effects

For the PNAS paper, Dr. Wallace and his team investigated the impacts of steadily increasing levels of a pathogenic mutation in one particular base of mitochondrial DNA. Researchers already knew that if 10 to 30 percent of a person’s mitochondrial DNA has this mutation, a person has diabetes, and sometimes autism. Individuals with an mtDNA mutation level of 50 to 90 percent have other multisystem diseases, particularly MELAS syndrome, a severe condition that involves brain and muscle impairments. Above the 90 percent level, patients die in infancy.

The investigators analyzed cultured human cells with different levels of this pathogenic mtDNA mutation to determine the effects on the gene expression of the cell. The researchers measured variations in cellular structure and function, nuclear gene expression, and production of different proteins.

Dr. Wallace argues that the medical significance of this research extends beyond the province of the relatively rare disorders typically classified as mitochondrial diseases. The gene expression profile—the pattern of gene activity seen at the level at which mtDNA mutations trigger brain disorders—parallels the profiles found in Alzheimer, Parkinson, and Huntington diseases. “The findings in this study provide strong support for the concept that common metabolic diseases such as diabetes and obesity, heart, and muscle diseases, and neurodegenerative diseases have underpinnings in energy deficiencies from malfunctioning mitochondria,” he said.

Significantly, Dr. Wallace added that the research also pertains to aging. Because mitochondrial mutations accumulate as people age, mitochondrial energy production declines, with deleterious effects on the heart, the brain and on interrelated biological systems that sustain health and life.

Future investigations will examine how different diseases are associated with the sorts of abrupt phase changes his group found in the current cellular study, Dr. Wallace noted. Some of the findings noted in the current research might become useful biomarkers in disease studies and drug development.

To read more about this landmark study, see the October issue of Bench to Bedside.