Well, it does not get any clearer than the findings of the study below. Namely, the old saying is true – we don’t see things the way they are, we see things the way we are. More specifically, the study claims that the positivity/negativity of our life experience and outlook on the world depend mostly on energy production in the brain, with the effects being bidirectional. Apparently, brain energy production is extremely sensitive to the functioning of electron transport chain (ETC) Complex I, which oxidizes NADH back into NAD+. That process depends on the availability of FAD/FMN and Coenzyme Q10 (CoQ10), and is easily inhibited by a variety of physical, chemical and social factors. One of the most widely prescribed drugs worldwide – metformin – is a powerful inhibitor of Complex I. Chronic stress (even mild in intensity) not only inhibits Complex I, but also reduces its expression, thus causing structural deficits in the machinery that produces energy. The resulting reductions in energy production in the brain result in negative psychosocial experiences, which are perceived as stress by the brain, which leads to further decline in energy production, and so on. In other words, a perfect vicious cycle. The opposite also seems to be true. Good experiences increase energy production in the brain, resulting in positive world perceptions, leading to further increase in energy production, and so on. The study cites numerous other experiments demonstrating that many mental health issues (anxiety, depression, psychosis, mania, etc) can be reliably caused in animals by interfering with energy production in the brain. Thus, the epidemic of mental illness seen in Western countries is likely nothing more than a symptom of the chronic stress people in those countries are experiencing, despite the claims of their governments that everything is great and things are betting better by the day. Aside from trying to improve out lifestyle and reduce stress, which is very difficult to achieve for most people living a “modern” lifestyle, another option would be to supplement with things that support brain energy production and especially Complex I. Such substances include vitamin B2 (precursor to FAD/FMN), CoQ10 (the oxidized version – uniquinone – not ubiquinol), niacinamide (precursor to NAD+), aspirin, thyroid, etc.
https://pubmed.ncbi.nlm.nih.gov/38889126/
Study Links Stress to Mitochondrial Dysfunction in the Brain
“…For the first time, scientists have shown that the abundance of proteins needed for mitochondrial energy production in human brains is linked to perceived psychosocial experiences [1]. ”
“…One such factor, OxPhos protein abundance, relates to the amount of protein available for oxidation-phosphorylation reactions, which are at the core of mitochondrial energy production. In the dorsolateral prefrontal cortex (DLPFC), a brain area that is involved in executive functions and emotional regulation and is known to be sensitive to psychological stress, this factor showed marked correlation with both positive and negative psychosocial experiences. The positive psychosocial aspects most associated with increased OxPhos protein abundance were well-being and late-life social activity. On the opposite side of the scale, negative mood and negative life events had the biggest effect sizes. “Thus”, the paper notes, “both individual experiences (well-being and mood) and objectifiable factors (social activity and life events) relate to DLPFC brain mitochondrial biology.” The correlation was most notable for complex I, the largest and most upstream mitochondrial OxPhos enzyme. Psychosocial experiences accounted for 18% to 25% of the variance in the abundance of this protein. For reasons not yet fully understood, the brain is exceptionally vulnerable to complex I defects [2].”
“…Moving from proteomics to single-cell RNA sequencing enabled the researchers to take an even closer look and yielded intriguing results. The correlation between psychosocial scores and complex I was undetectable for neurons but strong for glia, the “helper” cells that facilitate proper neuronal functions, such as microglia, the brain’s resident immune cells. “This may be why chronic psychological stress and negative experiences are bad for the brain,” said Caroline Trumpff, assistant professor of medical psychology in the Department of Psychiatry at Columbia University and a lead author on the paper, “because they damage or impair mitochondrial energy transformation in the dorsolateral prefrontal cortex, the part of the brain responsible for high-level cognitive tasks.” These results do not come as a complete surprise. Scientists have already shown that in animal models, stress impairs mitochondrial function [3]. Moreover, this relationship appears to be bidirectional: the same group that authored this new study had found that differences in mitochondrial energy production capacity affect anxiety and social avoidance in rodents [4].”
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