Mitochondria Seen to Play Outsize Role in Stress Response

According to a new study published in the journal Proceedings of the National Academy of Sciences, mitochondria may play a previously unknown role in mind-body interactions. The findings, based on new investigations into stress responses, may carry implications for the biology of psychiatric and neurological diseases, as well as for human psychology.

In humans and animals, stress triggers multisystemic physiological responses that vary in nature and magnitude. The organism’s response to stress, rather than the actual stressors, leads to stress that predisposes to disease. In the study titled “Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress,” Dr. Douglas C. Wallace and colleagues demonstrated, in animals, how alterations in mitochondrial function result in different physiological changes in metabolic, behavioral, and hormonal 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 Dr. Wallace, director of the Center for Mitochondrial and Epigenomic Medicine at The Children’s Hospital of Philadelphia, in a recent press release. “This has profound implications for the hereditary basis of neuropsychiatric diseases and for the role of stress in human health.”

Dr. Wallace, an expert in mitochondria genetics and their role in health, has long claimed that a conventional biomedical approach concentrated on anatomy (organ with disease symptoms) does not take into account the role played by bioenergetics in health and the relevance of systematic alterations in energetic metabolism. Mitochondria are at the core of bioenergetics, as they are the cellular organelles where energy for the body is produced.

In its research, the team exposed mice to standardized psychological stress by placing the animals in restraint for a short period of time. Scientists assessed the consequences of this psychological stressor on the mice’s inflammatory, metabolic, neuroendocrine, and gene transcription systems. All these systems are involved in behavioral stress responses and in long-term vulnerability to stress-related diseases.

The results showed that in the mice, mild mutations in the mitochondrial genes caused stress responses throughout the body, evident in physiological and gene expression patterns, suggesting that mitochondrial genetic variation can result in differential stress responses.

Although scientists have long recognized the role of individual differences in response to environmental factors such as stress, the identification of the physiological and genetic origin of these differences remains to be clarified.

“The brain, constituting only 2 percent of human body weight, consumes 20 percent of the body’s energy,” said Dr. Wallace. “Hence, mild variations in mitochondrial bioenergetics will have significant effects on the brain.”

Dr. Wallace believes that more research is needed to understand the associations between mitochondria and human behavior. “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,” the research team wrote. “In this emerging paradigm, mitochondria are at the interface of genetic and environmental factors contributing to disease trajectories.”

The team believes that the finding that altered mitochondrial states are linked to neuropsychiatric syndromes may help develop new and more effective treatments for these conditions, possibly allowing doctors to more successfully improve the effects of environmental stressors on human health, and reduce the burden of stress-related diseases.

Dr. Wallace concluded: “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.”