Mitochondria Affect How We Respond to Stressful Environments

Feeling frazzled and run down seems as synonymous as mistletoe and holly with the holidays. New research suggests that the tiny structures inside our cells that generate energy, called mitochondria, may play a role in our mind-body interactions and how we respond to stressful environments, such as jam-packed shopping malls.

Douglas C. Wallace, PhD, a pioneering scientist in mitochondrial medicine and director of the Center for Mitochondrial and Epigenomic Medicine at The Children’s Hospital of Philadelphia, has led research in animals showing how alterations in mitochondrial function lead to distinct physiological changes in hormonal, metabolic, and behavioral systems in response to mild stress. While researchers have long recognized individual differences in response to environmental cues such as stress, identifying the genetic and physiological basis for these individual differences has eluded scientists.

The researchers subjected the mice to a standardized psychological stress: placing them in restraint for a brief period. They then measured the effects of this stressor on the animals’ neuroendocrine, inflammatory, metabolic, and gene transcription systems. In humans, all of these systems are involved in behavioral responses to stress. Frequently activating stress responses can inflict long-term damage in mammals and humans. The cumulative wear and tear on the body can result in both psychological disorders and human diseases such as diabetes and age-related cognitive decline.

In the mice, relatively mild mutations in mitochondrial genes, located in either mitochondrial DNA (mtDNA) or nuclear DNA, produced unique whole-body stress-response signatures, indicated by physiological and gene expression patterns. mtDNA code for essential energy genes and exchange biological signals with the more familiar DNA housed in the cell nucleus. Those interactions affect physiological networks essential for health.

“This has profound implications for the hereditary basis of neuropsychiatric diseases and for the role of stress in human health,” Dr. Wallace said of the study that he published with colleagues in Proceedings of the National Academy of Sciences.

Although he emphasized that much more research remains to be done on the role of mitochondria on human behavior, Dr. Wallace postulated that the study indicates that an important reason for our limited progress in understanding the genetic and biologic basis of psychology is our lack of appreciation for the importance of systematic alterations in energetic metabolism. Dr. Wallace pointed out that while the brain constitutes only 2 percent of human body weight, it consumes 20 percent of the body’s energy; therefore, mild variations in mitochondrial bioenergetics could have significant effects on the brain.

“Scientists have long known that stressful experiences, on their own, do not cause disease; it’s our responses to stress that have the potential to culminate in disease,” Dr. Wallace and colleagues stated. “In this emerging paradigm, mitochondria are at the interface of genetic and environmental factors contributing to disease trajectories.”

Identifying the altered mitochondrial states associated with neuropsychiatric diseases may help suggest new therapies. These may permit physicians to more effectively ameliorate the effects of environmental stressors on human health and help people become more resilient in environmental changes.

In addition to his CHOP position, Dr. Wallace is on the faculty of the Perelman School of Medicine at the University of Pennsylvania. His co-authors are from CHOP, Penn, Thomas Jefferson University, and Rockefeller University.