Life Experiences May Shape the Activity of the Brain’s Cellular Powerhouses

Life Experiences May Shape the Activity of the Brain’s Cellular Powerhouses

Mitochondria appear to ratchet up their activity when life is going well and tamp it down during hard times

Illustration of mitochondria cells with a green background

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Caroline Trumpff, an assistant professor of medical psychology at the Columbia University Irving Medical Center in New York City, has long been interested in the mind-body connection. While many studies have provided evidence for this link, it’s still rare to see this knowledge applied to clinical practice, she says. That is because it remains difficult to trace a direct path from life circumstances—an extended network of family and friends or, by contrast, a difficult childhood—to what is going on at the molecular level. These gaps are why Trumpff has taken an interest in mitochondria. By investigating how these tiny cellular structures mediate the effects of mind on body and body on mind, she hopes to convince people to take the role of psychosocial factors on health more seriously.

Understanding mitochondria is a good place to start. Mitochondrial problems may be a culprit in a wide range of brain disorders and diseases, ranging from schizophrenia to Parkinson’s disease. But what causes problems in our mitochondria? Evidence from past studies, mostly in animals, has pointed to psychological stress as a key factor.

To investigate the relationship between mental states and mitochondria, Trumpff and her colleagues analyzed data from the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP)—two large, ongoing assessments of aging and dementia that have recruited thousands of individuals aged 65 and older across the U.S. For these studies, known collectively as ROSMAP, researchers continuously track participants’ mental and physical health—and, after death, examine their donated brain.

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For Trumpff’s study, the team looked specifically at whether there was a relationship between participants’ reported life experiences and the characteristics of mitochondria within the dorsolateral prefrontal cortex, a region of the brain involved in emotion regulation and executive functions, such as problem-solving and planning. Life experiences included those associated with better mental health (such as feeling purpose in life and having a large social network) and those with a negative impact on psychological well-being (such as adverse childhood experiences and social isolation).

The researchers’ analysis, which included data from 400 ROSMAP participants, revealed that positive experiences were most closely associated with a greater abundance of mitochondrial complex I, a key group of proteins involved in oxidative phosphorylation, the process by which mitochondria generate energy. Negative experiences, on the other hand, were associated with a lower abundance of the same protein complex. The results were published on June 18 in Proceedings of the National Academy of Sciences USA.

These findings, Trumpff says, suggest that our experiences may have an influence on how this minute cellular component can change its activity—ratcheting energy production up or down—in response to varying life circumstances. This chain of events might also go in the opposite direction: differences in the functioning of mitochondrial machinery could influence mental health in ways that determine what types of experiences a person will have. Trumpff says it’s likely that both things are happening because prior studies—mostly in rodent brains—have demonstrated both that chronic stress can alter mitochondria and that mitochondrial defects can alter behavior.

Previous work examining mitochondria outside the brain also support these results. In 2018, for example, Martin Picard, a mitochondrial psychobiologist at Columbia and a co-author of the latest study, found that people’s mood and stress levels affected the functioning of mitochondria in immune cells known as leukocytes. (Immune cells are commonly used in this type of study because they are found in blood, making them easier to access than brain cells, which can typically only be studied after death.) Researchers have also found signs of mitochondrial dysfunction in individuals with mental health disorders such as depression.

“The findings of this study highlight the significant impact that psychosocial factors—positive and negative experiences—may have on brain mitochondrial function,” says Audrey Tyrka, a translational scientist who studies stress, trauma and resilience at Brown University and was not involved in this work. “We know that, in turn, can influence cognitive function, psychiatric conditions and general well-being.” It is important, she adds, to conduct a similar analysis in a more diverse sample. Because 98 percent of the participants were white, this study cannot address any potential race- or ethnicity-specific issues, such as stress exposures arising from systemic racism and associated health disparities, Tyrka says.

Because the ROSMAP participants were all aged 65 and older when the study began, another open question is whether a similar relationship between life experiences and the functioning of brain mitochondria exists in younger individuals. In previous work, Iris-Tatjana Kolassa, a clinical biopsychologist at the University of Ulm in Germany, and her colleagues found that in adult women, childhood trauma was associated with increased, not diminished, mitochondrial energy production in immune cells after childbirth.

One explanation for this discrepancy, according to Kolassa, is that her study looked at the postpartum period, which is typically a stressful time that is also associated with inflammation. The way that mitochondria respond during such events might be different than during a normal state. Another possibility is that stress might lead to increased mitochondrial energy production in the short term—and, over time, this could lead to wear and tear that results in decreased mitochondrial capacity in older age. It may also be that mitochondria in immune cells react differently than those in the brain, according to Trumpff.

Although more research is needed to confirm the psychosocial-mitochondrial link that Trumpff’s team found, the study itself is a provocative finding that adds to the growing body of evidence indicating that states of mind and prior experiences such as early-life trauma can shape mitochondrial function, says Vidita Vaidya, a neuroscientist at the Tata Institute of Fundamental Research in India, who was not involved in the work. “At the moment, the jury is still out on causality—but there’s something here that’s really intriguing and worth exploring further.”

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