Is Mitochondria The Key That Unlocks Brain Health?

Cells with nuclei in blue, mitochondria in green, and cytoskeleton in red. Photo: NICHD via CC BY 2.0.

When we think of the early days of evolution — we’re usually always thinking of some time in the Pleistocene, when our ancestors, the hominids, still had fur and began to migrate across continents in search of quarry — or we think of that day eons ago when fish first crawled out of the water and touched dry land.

Yet, one of the most important evolutionary moments in the history of our planet occurred much earlier than this — when our oldest primordial ancestor, a singular, free-floating amoeba, swallowed an ancient bacterium. Over a billion years later, this encounter is still encoded in our DNA. The large bacterium offered a large, insular home, and the amoeba transformed into a powerhouse — the mitochondrion, carrying out the chemical processes necessary for cells to live and divide.

Equipped with their own sets of DNA, mitochondria are both a crucial part of our cells and a list of potential problems waiting to happen. The mitochondrial DNA harbors a number of mutations that can be provoked by any number of factors — even seemingly benign ones like age or stress. Damage to the mitochondria can also release unrecognizable molecules that the immune system mistakes for foreign invaders. Perhaps no other organ is more vulnerable to mitochondrial damage than the brain.

“The more energetically demanding a cell is, the more mitochondria they have, and the more critical that mitochondria health is — so there’s more potential for things to go wrong,” according to Dr. Andrew Moehlman, a postdoctoral researcher who specializes in the field of neurodegeneration at the National Institute of Neurological Disorders and Stroke. With the brain being the body’s ultimate powerhouse — a vast switchboard sending out trillions of messages on a daily basis, it is estimated that each of the brain’s neurons could contain as much as 2 million different structures of mitochondria.

For this reason, there is a steadily growing number of neuroscientists looking at the role this organelle plays in our overall brain health. An increasing body of literature, looking at both humans and lab animals — though much of it still preliminary — suggest these organelles could play a part in nearly every recognized brain disorder, from neurodevelopmental conditions like autism, psychiatric illnesses such as depression and schizophrenia, and neurodegenerative diseases like Parkinson’s. More importantly, they could even offer light on how external factors in the environment shape an individual’s cognitive development.

When The Powerhouse Shuts Down

Back in the 1960s, researchers first learned that the genetic material found in mitochondria was unique from the cell that harbored it. Later studies found that mitochondrial DNA, similar to that found in bacteria, consists of a circular strand, coding for just 37 genes — comparatively small when compared against the tens of thousands of genes found in the human genome. One decade later, a young researcher at Yale University by the name of Dr. Douglas Wallace, proposed that since these structures are so crucial to providing cellular energy, alterations would lead to disease.

Since the late 1980s, researchers have found connections between mitochondrial DNA alterations and dozens of clinical disorders, nearly all of which are neurological in nature. Wallace, who is currently director of the Children’s Hospital of Philadelphia’s Center for Mitochondrial and Epigenomic Medicine, weighs in on why this is: Even though it accounts for only 2% of our body weight, the human brain requires about one-fifth of the body’s energy in order to function. Therefore, even slight disruptions in the organelle can have massive consequences for the brain.

Wallace’s study interests include the role that mitochondria might play in autism spectrum disorders. Several research teams have published research indicating that mitochondrial diseases tend to occur much more often in people with autism (5%) than they do in the general population (about a 0.01% chance of occurrence). Between 30% to 50% of children with autism also exhibit signs of mitochondrial dysfunction — they may have abnormal levels of ATP, for example.

In some people on the spectrum, scientists have discovered genetic differences in either their mitochondrial DNA, or within several of the thousand genes found in the human genome that are known to determine mitochondrial function. There is, of course, still more study to be done in order to understand what role the genetic variations have in causing or adding to autism, if any, but a recently conducted study using lab mice suggests the possibility of a link. Wallace and his colleagues co-authored a study in the Proceedings of the National Academy of Sciences demonstrating that a specific mutation within mitochondrial DNA can produce autism-like traits in mice — such as muted social interactions, skittishness and even compulsive behaviors.

Unexpected genetic alterations, however, aren’t necessarily the only way in which mitochondria could play a role in the onset of autism. Environmental factors, like the presence of toxic pollutants, have also been linked to a greater risk of developing spectrum disorders.

Dr. Richard Frye, who is a pediatric neurologist and autism researcher from the Phoenix Children’s Hospital of Arizona, and his colleagues have discovered that the concentration of air pollution that children with autism were exposed to prior to being born changed the degree at which their neurons’ mitochondria developed ATP. In a subsequent experiment, Frye’s team noticed a correlation between early-life exposure to toxic metals like lead, and how capable mitochondria worked in people with autism later in their lives. He thinks this is fairly compelling evidence, but he hasn’t grown content just yet.

“It’s too soon to make any firm conclusions about a lot of this stuff, but it sure looks like the mitochondria are disrupted in many kids with autism,” said Frye. “And environmental exposures, especially early on, may be programming the mitochondria to have different types of respiratory physiology.”

Mitochondria For Every Purpose

Aside from producing the ATP that cells need to function, they have a number of crucial purposes that are deepening our understanding of neurobiology. They work as a buffer for balancing toxic cellular byproducts known as reactive oxygen species and they help produce crucial stress hormones such as cortisol, which responds to inflammation and metabolism.

These organelles are hardly isolated in their processes either, interacting with other mitochondria through the use of signaling molecules, nor do we always see them in the same state. Indeed, they are continuously going through processes of fission, in which a large mitochondrion structure breaks off as two smaller ones, or a fusion process, wherein they combine. This continuous cellular process is still an enigma to scientists who believe it must inevitably play a role in brain function.

Dr. Carmen Sandi, a behavioral neuroscientist who works for the Swiss Federal Institute of Technology, and her research team have analyzed mitochondrial structures in lab mice who display high levels of anxiety — such as reluctance to spend large amounts of time in open spaces. In the brains of these anxious rodents, mitochondria found in the neurons of the nucleus accumbens, which is a brain area involved in processing reward, had diminished levels of ATP production, compared to their less anxious counterparts. The high-anxiety mice also exhibited reduced levels of an enzyme critical to the fusion process. Boosting the protein not only brought mitochondrial function back to normal levels, but also reduced the anxious behaviors of the mice.

Discoveries like these are reasons for researchers like Wallace to be hopeful. Already, his colleagues are experimenting with potential treatments to bolster the function of mitochondria — both medications and even new behavioral treatments. Frye is currently at work on a clinical trial investigating the ability of nutritional supplements to reverse mitochondrial damage in children with autism. It will take time, but the wide array of functions carried out on the mitochondrial level are giving researchers hope for the future.

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1 Comment

  1. I believe you have a transposition when you said: Yet, one of the most important evolutionary moments in the history of our planet occurred much earlier than this — when our oldest primordial ancestor, a singular, free-floating amoeba, swallowed an ancient bacterium. Over a billion years later, this encounter is still encoded in our DNA. The large SHOULD BE AMOEBA offered a large, insular home, and the SHOULD BE BACTERIUM transformed into a powerhouse — the mitochondrion, carrying out the chemical processes necessary for cells to live and divide.

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