Psychological Stress and Mitochondria: A Systematic Review

Abstract

Objective: Mitochondria are multifunctional life-sustaining organelles that represent a potential intersection point between psychosocial experiences and biological stress responses. This article provides a systematic review of the effects of psychological stress on mitochondrial structure and function.

Methods: A systematic review of the literature investigating the effects of psychological stress on mitochondrial function was conducted. The review focused on experimentally controlled studies allowing us to draw causal inference about the effect of induced psychological stress on mitochondria.

Results: A total of 23 studies met the inclusion criteria. All studies involved male laboratory animals, and most demonstrated that acute and chronic stressors influenced specific facets of mitochondrial function, particularly within the brain. Nineteen studies showed significant adverse effects of psychological stress on mitochondria and four found increases in function or size after stress. In humans, only six observational studies were available, none with experimental designs, and most only measured biological markers that do not directly reflect mitochondrial function, such as mitochondrial DNA copy number.

Conclusons: Overall, evidence supports the notion that acute and chronic stressors influence various aspects of mitochondrial biology, and that chronic stress exposure can lead to molecular and functional recalibrations among mitochondria. Limitations of current animal and human studies are discussed. Maladaptive mitochondrial changes that characterize this subcellular state of stress are termed mitochondrial allostatic load. Prospective studies with sensitive measures of specific mitochondrial outcomes will be needed to establish the link between psychosocial stressors, emotional states, the resulting neuroendocrine and immune processes, and mitochondrial energetics relevant to mind-body research in humans.

FIGURE 1

Mitochondrial structures, functions, and their positioning within the cell. (Center) Psychosomatic medicine research aims to understand how psychosocial and behavioral exposures including stress influence biological and physiological processes across the organism, including those inside the cell nucleus where genes are transcriptionally and epigenetically regulated. Mitochondria are positioned in the cell cytoplasm at the interface between psychosocial and behavioral factors and the cell nucleus. (Left) Detailed cartoon of mitochondrial structures, including the electron transport chain (respiratory chain) illustrating the flow of energy from nutrients to the pumping of protons (H⁺) to generate membrane potential, in part used to synthesize ATP, the energy currency of the cell. This process generates ROS, which are detoxified by specific mitochondrial antioxidant enzymes. (Right) Magnification of the mito-nuclear interface in a pseudo-colored electron micrograph showing the physical proximity between the chromatin in the nucleus and mitochondria (22). Mitochondria also communicate with each other via IMJs, nanotunnels, and other mechanisms (23). Signals derived from mitochondrial metabolism interact with other biochemical factors to coordinate gene expression and telomere maintenance via transcriptional and epigenetic mechanisms (–26). ROS = reactive oxygen species; IMJs = intermitochondrial junctions; mtDNA = mitochondrial DNA; TCA = tricarboxylic acid; ATP = adenosine triphosphate. Color image is available only in online version (www.psychosomaticmedicine.org).

FIGURE 2

The human mitochondrial genome (mtDNA). The mtDNA contains 16,569 nucleotides and encodes 37 canonical genes, including 2 rRNA and 22 tRNA required for protein synthesis. Encoded proteins constitute part of the respiratory chain and include seven subunits of complex I, one subunit of complex III, three subunits of complex IV, and two subunits of complex V. Other mtDNA-encoded mRNA transcripts giving rise to secreted mitokines have also been described (28). The mtDNA is composed of light (inner circle) and heavy (outer circle) mtDNA strands. The mtDNA is replicated from two origins of replication on the light and heavy strands termed O_L and O_H, respectively. mtDNA gene expression is initiated from promoters on the heavy strand (P_H1 and P_H2) and on the light strand (P_L). The glucocorticoid receptor and other transcription factors interact with the mtDNA near the D-loop (29). Ethnic differences exist in mtDNA sequence (31,32). Note that colors for each gene are matched to the respiratory chain complexes, of which they encode a subunit in Figure 1. mtDNA = mitochondrial DNA; rRNA = ribosomal RNA; tRNA = transfer RNA; mRNA = messenger RNA; ATP = adenosine triphosphate. Color image is available only in online version (www.psychosomaticmedicine.org).

FIGURE 3

Flow diagram for study selection in the systematic review. See “Methods” for details.