Mitochondria affect stress responses

A pioneering scientist in mitochondrial medicine 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.

"Our findings suggest that relatively mild alterations in mitochondrial genes, and hence mitochondrial physiology, have large effects on how mammals respond to stressful changes in their environment," said Douglas C. Wallace, Ph.D., director of the Center for Mitochondrial and Epigenomic Medicine at The Children's Hospital of Philadelphia. "This has profound implications for the hereditary basis of neuropsychiatric diseases and for the role of stress in human health."

Wallace and colleagues published their study ahead of print on Nov. 16 in Proceedings of the National Academy of Sciences.

Wallace, who has investigated the genetics of mitochondria and their role in health for over 40 years, has long argued that a traditional biomedical approach focused on anatomy and thus, on the organ exhibiting the most prominent symptoms of a disease, overlooks the key role played by systematic bioenergetics in health. At the core of bioenergetics are the mitochondria, residing in large numbers outside the nucleus of every cell. Mitochondria contain their own DNA, which codes for essential energy genes and which exchanges biological signals with the more familiar DNA housed in the cell nucleus. Those interactions affect physiological networks essential for health.

In this current study, 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 and long-term susceptibility to stress-related diseases.

Wallace and colleagues showed that 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. These differential responses to stress due to mitochondrial variation provide a physiological explanation for a 2012 observation by Wallace's laboratory team. That research, published in Cell, involved mixing two normal but different mtDNAs in a mouse model, thus thwarting the usual strict maternal inheritance of the mitochondrial DNA. Simply mixing those two mtDNAs resulted in hyper-excitable mice with severe learning and memory defects.

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. Although he emphasizes that much more research remains to be done on the role of mitochondria on human behavior, Wallace postulates that the current 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. "The brain, constituting only 2 percent of human body weight, consumes 20 percent of the body's energy," he said. "Hence, mild variations in mitochondrial bioenergetics will have significant effects on the brain."

It is well known that frequently activating stress responses can inflict long-term damage in mammals and humans. Under the framework of mind-body connections, stress researchers refer to allostatic load: the cumulative wear and tear on the body that can result in both psychological disorders and human diseases such as diabetes and age-related cognitive decline.

As Wallace and associates point out, "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." They conclude, "In this emerging paradigm, mitochondria are at the interface of genetic and environmental factors contributing to disease trajectories."

One implication of this new study, said Wallace, is that 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. This could make people more resilient in environmental changes, reduce the long-term burden of stress-related diseases and produce more effective therapies for psychiatric disorders.

Wallace concludes, "While human differences in behavior and its relation to predisposition to mental illness as well as to a wide varied of pediatric and adult neurological diseases has been the subject of intense investigations for over a century, we still have a rudimentary understanding of the physiological, genetic, and environmental factors that mediate mental health and illness. Our recent papers strongly suggest that by reorienting our investigations from the anatomy of the brain and brain-specific genes to the mitochondria and the bioenergetics genes, we may have a more productive conceptual framework to understand neuropsychiatric disease. If so, this will spawn a whole new generation of neuropsychiatric therapeutics."