Brain disorders research

The plot of many thrillers is a vital secret from the past hidden in plain sight, a twist that upends everything we thought we knew. Now imagine that there is such a thing lurking in every human cell, something alien, billions of years old, and dictating our survival and evolution ever since. That curious something is the mitochondrion.

The Mystery of Mitochondria

The mitochondria are the energy centres of the cell and indispensable to complex life. But closer inspection reveals something very peculiar: mitochondria have DNA entirely distinct from the DNA of the cell itself. This separate DNA appears to come from a totally different species, in fact, a species as different from us as it is possible to be: bacteria. The hybrid present in every cell is as baffling as discovering a dinosaur with human hands.

The predominant theory to explain the anomaly reaches into the deepest past. Biologists postulate that a solitary single-celled organism – which after billions of years would evolve into us – had a momentary encounter that permitted all that followed.

This primitive ancestor engulfed a tiny bacterium which by some outrageous fluke was neither digested nor destroyed but hung around as an internal companion. The ingested bacterium endured unchanged through the aeons as the mitochondrion, while the larger organism was propelled into ever greater complexity and became Man.

The proposed process is both so crucial and so improbable that some thinkers have resorted to truly wild alternatives, such as the artificial tinkering of an alien or supernatural intelligence.

Whatever the cause, our bodies house trillions of these archaic descendants loyally churning out energy as the molecule ATP. We couldn’t be here at all without them, but their foreign origin has imparted a critical flaw.

Since mitochondria still carry bacterial DNA, whenever they are damaged and debris leaks outside the cells, the immune system may register an enemy and launch into an attack against its own tissues. The lucky symbiosis has brought with it the threat of friendly fire.

Such trade-offs are everywhere in the complex dance of evolution, such as the size of our brains meaning that infants must be born when still utterly helpless – otherwise a woman’s pelvis would need to be so large that she could no longer walk.

Our brains also require an enormous outlay of energy: only 2% of body weight, they consume around 20% of its energy. And what produces that energy? Mitochondria.

That means that our brains rely on a vulnerable power source, and even minor downturns in mitochondrial output can have severe consequences for brain function.

Mitochondria and Brain Disorders

Various studies implicate mitochondria in almost every brain disorder. In autism, for example, mitochondrial abnormalities are 500 times more common. More specific evidence currently comes from animal studies, such as one in mice which linked autistic behaviours (such as impaired socialising) to a particular mitochondrial mutation. More general indicators of mitochondrial dysfunction are seen in the human disorders of schizophrenia and depression.

Such findings remain correlations and not direct causes, which suggests that the identified mutations need another factor before they can appear as a disorder. Like almost every disease, the additional element appears to be an environment trigger.

One study showed that prenatal exposure to pollution reduced mitochondrial ATP production. Another study implicated metals such as zinc or lead. Higher levels of such toxins might explain why rates of autism have increased in developed societies. An increased rate of a particular disorder in one population suggests a shared environmental cause, while the fact that not everyone succumbs indicates that genetics must also be involved.

That pattern is familiar for many diseases but here we have a fascinating difference: mitochondria are so small and so ubiquitous that the usual distinction between genetics and function is blurred. That means that mitochondria may be the mysterious nexus point where genes and function (and perhaps environment too) converge.

To illustrate, imagine a book: usually there is a clear difference between the physical book and the story inside. That’s a neat image of genes and their function. On the other hand, mitochondria are like Kramer’s book idea in Seinfeld: a coffee table book about coffee tables, which also has pull-out legs so that it is itself its own coffee table. Damage a regular book and it may not tell its story as well, but damage Kramer’s coffee table book and it is no longer what it was at all.

So too with mitochondria: damage will not just reduce function but produce real physical effects from the genetic material itself – by triggering the immune system. What’s more, the unique placement of mitochondria at the heart of every cell means that the blurring of categories may go even deeper. The most fascinating implication of recent studies is that factors affecting mitochondria may not even be physical.

The Effect of Trauma and Emotional Experience

One particularly intriguing hint comes from the finding that survivors of childhood trauma have more mitochondrial DNA per cell. Perhaps emotional stress increases energy demands, or produces damage to the point that more mitochondria are required. Perhaps both processes are at play.

Whatever the case, the implication is that an emotional experience produces a real physical effect, and the point where the two worlds collide is in the mitochondria.

Once the system is stretched, further emotional turmoil may then overwhelm it completely. This is precisely the pattern often observed in psychiatric disorders: childhood trauma may lie dormant for years until an additional stress in adulthood – perhaps of a different kind entirely – and the result is depression, schizophrenia, indeed any of the psychiatric conditions. Which disorder emerges may have been determined long before when the mitochondrial damage occurred: in childhood, or even before birth.

But how exactly would mental stress cause physical damage?

The Role of Energy

Here we have the mind-brain problem that has befuddled philosophers for centuries. A better understanding of mitochondria may offer the beginnings of an answer, and it comes down to their role as the brain’s power source.

Energy is the phenomenon of reality that lies right at the border between the physical and the non-physical, and may in fact be the medium through which the material brain produces the immaterial mind. It certainly appears that way from observing the patterns of electrical current in a brain scan.

A simple explanation may be that mental stress stretches the energy production of mitochondria to the limit and, if prolonged, the mitochondria begin to break down – much like a car engine pushed too hard. That idea gels with the finding that childhood trauma leads to more mitochondria.

Further evidence comes from a study in 2019 (Picard et al.) that showed an increase in circulating mitochondrial DNA after public speaking. The authors concluded that the stress led to mitochondrial damage which then leaked out of the cells as debris.

While much remains to be understood, we can at least hypothesise that the point where the mental and physical interact is indeed the mitochondria. Rene Descartes thought that this mysterious nexus point was the pineal gland, and philosophers have been chuckling over his error ever since. Yet if these studies are accurate, Descartes may have on the right track: correct in postulating a mind / brain interface while being a little off with the location.

While proving links between emotional and cellular causes lies beyond current technology, we can be more certain about mitochondria’s link with the immune system.

Looking for Answers

A 2010 Harvard study showed that severe physical injuries result in a surge of mitochondrial DNA into the bloodstream, which in turn triggers a severe inflammatory response. The condition mimics an overwhelming bacterial infection, which is precisely what the immune system “thinks” is happening. Ironically, the result is often lethal, and a major focus of treatment is dampening the misguided immune response with steroids.

Another study showed that sometimes mitochondria can disgorge DNA even without injuries, such as when a key protein is lacking. Emerging research suggests that this phenomenon may be behind neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Amyotrophic Lateral Sclerosis. A related mechanism may be failure of the cell to clear damaged mitochondria, which seems to be the case in some forms of Parkinson’s disease.

Damaging mitochondria in mice has been shown to activate inflammation and then the death of dopamine cells: the hallmark of Parkinson’s. Meanwhile mutant mice without a key inflammatory molecule did not show the same effect.

One problem with this mitochondrial theory is that some level of damage is inevitable, yet not everyone develops these brain diseases. Perhaps the immune system can cope with a regular trickle of leaking DNA (just as it copes with billions of resident friendly bacteria), but goes haywire if there is a sudden surge – such as from a car accident, or severe mental trauma.

While most of us will avoid these large-scale triggers, what we cannot elude is the slow march of time. Behind the aging process may also lie the effect of mitochondria-induced inflammation. A recent study (West et al. 2020) showed that mice with unstable mitochondrial DNA aged faster, while deactivating the immune system brought their rate of deterioration back towards normal.

So far most mitochondria research has focused on where the system goes wrong, rather than finding ways to prevent or treat the problems that arise. There are, however, indications that the field may be maturing towards clinical applications.

Sandi et al. (2021) found that anxious mice have mitochondria that produce less ATP and have lower levels of an enzyme that allows mitochondria to fuse and thereby assist each other. Meanwhile, adding more of the enzyme both restored mitochondrial function and reduced anxious behaviours.

Evidence from other studies suggest that exercise and some nutrient supplements can boost mitochondrial function, even reversing some of the problems found in children with autism.

Findings such as these bolster the theory that mitochondria lie at the heart of many brain disorders, as well as offering hope that novel treatments are on the horizon. Research in the field may begin to illuminate the shared origin of the variety of mental disorders, and help explain why they so often occur together.