Your response to stress—hormonally, metabolically, and behaviorally—may depend on your mitochondrial genes. And so your mitochondrial genes may determine your long-term susceptibility to stress-related diseases. They may even have a role in human psychology and the biology of psychiatric and neurological diseases.

These possibilities were raised by a study that aligned mutations in mitochondrial genes with unique whole-body stress-response signatures. The study, which was conducted at the Children’s Hospital of Philadelphia, indicates that even relatively mild mutations in mitochondrial genes can cause systemic alterations in energetic metabolism, and that these alterations affect physiological networks essential for health, including physiological networks that affect the brain.

“The brain, constituting only 2% of human body weight, consumes 20% of the body's energy,” said Douglas C. Wallace, Ph.D., director of the Center for Mitochondrial and Epigenomic Medicine at the Children's Hospital of Philadelphia. “Hence, mild variations in mitochondrial bioenergetics will have significant effects on the brain.”

Dr. Wallace and colleagues settled on the hypothesis that abnormal mitochondrial functions in an organism would differentially modulate that organism’s multisystemic response to psychological stress. Then they tested this hypothesis. They subjected mice to a standardized psychological stress: placing them in restraint for a brief period. Next they measured the effects of this stressor on the animals' neuroendocrine, inflammatory, metabolic, and gene transcription systems.

Crucially, the mice used in this study sustained alterations in their mitochondrial genes, alterations that were designed to selectively impair mitochondrial respiratory chain function, energy exchange, and mitochondrial redox balance. Such alterations included mutations or deletions in the mitochondrial genes encoded in the mitochondrial DNA (NADH dehydrogenase 6 and cytochrome c oxidase subunit I) or nuclear DNA (adenine nucleotide translocator 1 and nicotinamide nucleotide transhydrogenase).

The results of the study appeared in the December 1 issue of the Proceedings of the National Academy of Sciences, in an article entitled, “Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress.” The article described how the mitochondrial gene changes impacted the physiological reactivity and recovery from restrain stress.

“When analyzed collectively, stress-induced neuroendocrine, inflammatory, metabolic, and transcriptional responses coalesced into unique signatures that distinguish groups based on their mitochondrial genotype,” wrote the article’s authors. In particular, mitochondrial dysfunctions altered the hypothalamic–pituitary–adrenal axis, sympathetic adrenal–medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress.

“These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key pathophysiological perturbations previously linked to disease,” the authors continued. “This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases.”

The study, said Dr. Wallace, could have profound implications for the hereditary basis of neuropsychiatric diseases and for the role of stress in human health. He added that identifying the altered mitochondrial states associated with neuropsychiatric diseases could suggest new therapies.

If such therapies were be devised, physicians would be able 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.

“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,” concluded Dr. Wallace. “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.”