Acute psychological stress increases serum circulating cell-free mitochondrial DNA, 2019, Picard et al

Andy

Andy

Retired committee member
No idea if this is good science or not, but thought it might be of interest.
Highlights

  • Circulating cell-free mitochondrial DNA (ccf-mtDNA) is released from mitochondria.
  • Ccf-mtDNA is a pro-inflammatory molecule elevated with aging and inflammatory diseases.
  • Psychological stress rapidly and selectively increases serum ccf-mtDNA, not ccf-nDNA.
  • The effect size for stress-induced elevation in serum ccf-mtDNA is larger in men.
  • Neuroendocrine signaling triggers mtDNA extrusion in primary human fibroblasts.
Abstract
Intrinsic biological mechanisms transduce psychological stress into physiological adaptation that requires energy, but the role of mitochondria and mitochondrial DNA (mtDNA) in this process has not been defined in humans. Here, we show that similar to physical injury, exposure to psychological stress increases serum circulating cell-free mtDNA (ccf-mtDNA) levels. Healthy midlife adults exposed on two separate occasions to a brief psychological challenge exhibited a 2-3-fold increase in ccf-mtDNA, with no change in ccf-nuclear DNA levels, establishing the magnitude and specificity for ccf-mtDNA reactivity. In cell-based studies, we show that glucocorticoid signaling – a consequence of psychological stress in humans – is sufficient to induce mtDNA extrusion in a time frame consistent with stress-induced ccf-mtDNA increase. Collectively, these findings provide evidence that acute psychological stress induces ccf-mtDNA and implicate neuroendocrine signaling as a potential trigger for ccf-mtDNA release. Further controlled work is needed to confirm that observed increases in ccf-mtDNA result from stress exposure and to determine the functional significance of this effect.
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Paywall, https://www.sciencedirect.com/science/article/pii/S0306453018312149
Sci hub, https://sci-hub.se/10.1016/j.psyneuen.2019.03.026
 
I guess it's not surprising that a psychological threat might result in the same response as a physical threat. And I guess it's useful to know that that response involves the ejection of mitochondrial DNA from cells.

However, the stressor in this case was 2 minutes preparation for a defence of an imaginary false allegation of shoplifting or a traffic incident, with 3 minutes delivering it. Therefore, it's arguable that it was just the cognitive demands of the task that caused the response. Supporting that idea is the fact that in the second session, when people were told that they had performed below average in the first session, there wasn't a bigger mitochondrial DNA response, as might be expected if psychological stress was the cause. Personally, I wouldn't be particularly stressed by this exercise; it has no serious consequence. A lot of people who are perfectly healthy would routinely deal with similarly demanding tasks every day.

The paper suggests that mitochondrial DNA is released in response to exercise, infection or physical injury. Maybe this signalling occurs in response to all sorts of stressors, mild or otherwise? Maybe a jog around the block or a game of scrabble cause the same response?
 
What surprised me was that this is news.

Having read and been told that your body does not differentiate between physical and psychological stress, that cortisol modulates over 300 genes, that in rat models stress is epigenetically expressed and for some genes heritable, i had perhaps assumed that this had been checked out before and signalling was more " known " .

I guess " never assume" is the takeaway from this.
 
Just had a thought - the participants fasted overnight and through the morning until after the trial. They had an IV catheter inserted into the antecubital fossa of one arm and had three blood samples taken. Who knows if any of that had more of an impact than giving a 3 minute presentation?

Not the authors of this study because they had no controls.
 
Great points, @Hutan.

I do wonder why these stress studies never include any sort of control for the non-stress elements of the task. For a start, how about walking once around the block or collecting up some cushions from the floor?

These days I wonder whether the whole idea of psychological "stress" just ties us in knots and gets us nowhere. Its such a vague concept. Something to do with psychological demands that a person has difficulty meeting. There seem to be so many different types of situations that count as stressful, and they don't have that much in common. I wonder if it would be more useful to use specific terms - like "pressure to perform", "experiencing negative feedback", "enduring discomfort" and so forth.

Getting rid of the term psychological stress and replacing it with more specific things might help to prevent the inevitable slide between psychological and physiological/biological forms of stress.
 
Hutan said:
Just had a thought - the participants fasted overnight and through the morning until after the trial. They had an IV catheter inserted into the antecubital fossa of one arm and had three blood samples taken. Who knows if any of that had more of an impact than giving a 3 minute presentation?

Not the authors of this study because they had no controls.
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Indeed. It is inappropriate to derive conclusions from pilot studies like this.
 
There was an article on this research in Scientific American last September: Brain’s Dumped DNA May Lead to Stress, Depression
The genetic cast-offs are not just inert cellular waste. “This circulating mitochondrial DNA acts like a hormone,” says Martin Picard, a psychobiologist at Columbia University, who has been studying mitochondrial behavior and the cell-free mitochondrial DNA for the better part of the last decade.
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But how was this inflammation triggered by mitochondrial DNA leaking out of cells? A 2010 Nature paper provided the answer: In it researchers demonstrated the way mitochondrial DNA, when released into the blood after an injury, mobilized a pro-inflammatory immune response. Because of mitochondria’s bacterial origin and its circular DNA structure, immune cells think it’s a foreign invader. When circulating mitochondrial DNA binds to a particular receptor, TLR9, on immune cells, they respond as if they were reacting to a foreign invader such as a flu virus or an infected wound. The immune cells release chemicals called cytokines telling other white blood cells they need to report for duty at sites of infection, inflammation or trauma.
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The article doesn't get into this, but could the biological stress caused by the immune system's reaction to mitochondrial DNA in the bloodstream wind up causing the release of more mDNA into the bloodstream? So, following some kind of significant triggering event, like an infection, could you wind up in a loop where there's enough mDNA being released into the bloodstream to become self-perpetuating?
 
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