In recent study, a team of researchers from the University of Pennsylvania and Rockefeller University hypothesize that abnormal mitochondrial functions could affect — by differentially modulating — an organism’s multisystemic response to psychological stress. The article, published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS), is titled “Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress.”
The experience of psychological stress triggers neuroendocrine, inflammatory, metabolic, and transcriptional reactions that eventually predispose an individual to disease. However, the sub cellular determinants of this multisystemic stress response have not been defined. Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress.
Mitochondria are symbiotic organelles that contain their own genetic material, the mitochondrial DNA (mtDNA), which encodes essential subunits of the respiratory chain complexes I, III, IV, and V. At complex I, electrons derived from energetic substrates (glucose and lipids) enter the respiratory chain and travel to complex IV, where they are combined with oxygen to produce energy in the form of ATP. The ATP generated inside mitochondria is then exported across the inner mitochondrial membrane into the cytoplasm by adenine nucleotide translocators 1 and 2 (ANT1 and 2), where it fuels most energy-dependent cellular reactions.
In the study, the research team used mice with mutations in mtDNA genes that decrease the activity of the respiratory chain complexes. The team also studied mice with genetic deletions that impair ATP transport from the mitochondrion to the cytoplasm, and that control the intramitochondrial redox balance.
The scientists investigated the impact of these genetic manipulations on physical parameters associated with the restraint of stress and found that mitochondria has stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases.
The authors wrote, according to a news release, “All investigated neuroendocrine, metabolic, inflammatory, and transcriptional responses were perturbed by at least one of the mitochondrial defects. Notably, each mitochondrial defect produced a unique stress-response signature. Collectively, our results therefore establish that mitochondria impact the nature and magnitude of physiological and molecular responses to a controlled psychological stressor.”
In order to be successfully adaptive, organisms mount integrated stress responses across multiple organ systems. The ability to effectively respond to psychological stress is vital for survival, and is considered a driver of the evolution of species. Maladaptive stress response in humans causes chronic stress characterized by distinct symptoms, and eventually leads to disease.
“Stressful experiences, on their own, do not cause damage or disease,” the authors wrote. “Rather, it is the organism’s responses to stress that have the potential to result in physiological dysregulation and dysfunction, culminating in allostatic load and disease. Our study demonstrates how mitochondria can shape the major stress-response pathways, thereby recalibrating the multisystemic response to psychological stress.”
According to the researchers, mitochondria lie at the interface of genetic and environmental factors contributing to disease trajectories. They suggest that targeting mitochondria may open new avenues to promote biological resilience, and to understand further the bioenergetic and allostatic mechanisms by which environmental stressors promote disease across a person’s lifespan.