Billions of years before the appearance of the earliest animals in the ancient oceans, a key development took place. A solo, free-floating cell overtook a primitive bacterium. They fused together in a mutually beneficial relationship that has continued to this day. The cell provides the fuel for life, and the bacterium provides a safe haven.
The above explanation is a hypothesis for how the organelles, or cellular components, known today as mitochondria came to exist. Today, trillions of these organisms live in our body producing ATP, the molecular energy source that feeds our cells. While mitochondria are integrated with our body systems, they also retain remnants of their bacterial origins such as its own set of DNA.
The DNA of our human genome is in the nucleus of our cells. However, mitochondria have their own circular DNA, which likely remains from their past as a bacterium. This makes mitochondria a key feature of our cells but also a potential source of complication. Mitochondrial DNA may contain mutations, just as our DNA can contain mutations. Many factors can disrupt the functions of the mitochondria like age and stress. In addition, the mitochondrial injury may result in the release of molecules that our own immune system mistakes as foreign invaders, thus initiating an inflammatory response against our own cells.
Our brains are particularly susceptible to mitochondrial damage. “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,” says Andrew Moehlman, a postdoctoral researcher who studies neurodegeneration at the US National Institute of Neurological Disorders and Stroke (NINDS). According to some estimates, each neuron can have up to 2 million mitochondria.
A small but grown contingent of researchers is studying the contributions of mitochondria to brain health. While still in the preliminary stages, studies in animals and humans suggest that organelles may be involved in every type of brain disorder, including neurodevelopmental conditions like autism, neurodegenerative diseases like Parkinson’s, and psychiatric illnesses like depression and schizophrenia. They may also provide clues into genetic predispositions and environmental influences that increase the risk of developing these conditions.
Problems within mitochondria
In the 1960s, scientists found that mitochondria have a unique set of genetic material. Mitochondrial DNA contains a circular strand of DNA that encodes only 37 genes, which represents a tiny fraction of the tens of thousands contained in the human genome.
In the 1970s, Douglas Wallace, a doctoral student at Yale, studies mitochondrial DNA. He hypothesized that since mitochondria were the primary producers of the body’s energy, mutations in their DNA would lead to disease. Other researchers did not accept that hypothesis at first. However, he and his colleagues established a link between a mutation in mitochondrial DNA and human disease in 1988. The disease was Leber’s hereditary optic neuropathy, which causes sudden blindness. After that discovery, other scientists took interest in Wallace’s work.
Now, researchers have linked many disorders to a mutation in both mitochondrial DNA and nuclear DNA related to mitochondrial function. Most of these disorders are neurologically related or have some effect on the brain. This may be because our brain uses about one-fifth of the body’s energy while being only about 2% of the total body weight of an individual. A small decrease in mitochondrial function can have a huge impact on brain health and functioning.
The brain’s waste removal system
Now studies are looking into whether mitochondria may contribute to autism spectrum disorder (ASD). Some of these studies have shown that mitochondrial disease is much more prevalent in people with autism – about 5% – versus a prevalence of about 0.01% in the general population. Approximately 30% to 50% of children on the spectrum show signs of mitochondrial dysfunction, like abnormal levels of specific byproducts generated by cellular respiration, which is how ATP is produced.
In individuals with autism, scientists have pinpointed genetic differences involving mitochondrial DNA and some genes in the human genome that influence mitochondrial function. More studies are needed to confirm whether these variations cause or contribute to autism. However, a recent study using mice suggests that there may be a link. That study showed that a specific mutation in mitochondrial DNA led to autism-like trains in mice such as impaired social interactions, compulsive behaviors, and skittishness.
Genetic mutations may not be the only way that mitochondria may contribute to autism. Some environmental factors, like toxic pollutants, have been linked to a higher risk of developing autism. These environmental factors may disrupt the health of mitochondrial health in people with autism. One study examined the levels of air pollution that children with autism were exposed to in utero. The report showed alterations in the rates at which their mitochondria generated ATP. The study also found links between early-life exposure to beneficial metals like zinc and toxic metals like lead. These findings may ultimately suggest that mitochondria are the missing link between autism and environmental influences that contribute to autism.
Scientists are also finding signs of mitochondrial dysfunction, like changes in the way they metabolize sugars to produce energy, in individuals with people suffering from depression and schizophrenia. Other reports suggest that mitochondria may be sensitive to a risk factor for many mental disorders, which is psychological stress early in life.
For instance, people who have experienced a traumatic event in childhood appear to have a larger number of mitochondrial genomes per cell. This increase, which can also indicate the production of new mitochondria, may happen to compensate for problems in the organelle.
While mitochondrial dysfunction occurs in a broad range of brain disorders, it’s not clear if the dysfunction is the primary cause of the condition or a secondary effect. Still, studying the issues may lead to innovation in therapeutics that target mitochondria that may benefit the patient even if they don’t cure the condition.
When mitochondria attack the system
When mitochondria become dysfunctional or damaged, it may result in less ATP and less energy for the normal function of the brain. However, another way that mitochondria may contribute to brain disorders finds their origins in their bacterial past.
Mitochondria have DNA and other elements that may be released when cells become injured or stressed. Our immune systems may mistake them as a foreign threat. In 2010, researchers at Harvard University reported a rapid release of mitochondrial DNA into the bloodstream in people with severe physical injuries. This attracted immune cells and triggered a severe inflammatory response that mimicked sepsis — a life-threatening condition in which the immune system attacks the body’s own tissues.
Several years later, A. Phillip West, a postdoctoral candidate at Yale, and his colleagues found that DNA can leak out of mitochondria and activate the immune system in without the presence of severe physical injuries, such as when the organelles experienced a deficiency in a key protein.
Inflammation caused by the release of mitochondrial DNA may contribute to the damage found in neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS), according to a growing number of studies. In separate lines of research, scientists have linked these disorders with both inflammation and an inability to properly rid cells of defective mitochondria. Mitochondria-triggered inflammation may be the missing link between the two.
For instance, mutations in 2 genes linked to certain forms of inherited Parkinson’s disease, PINK1 and PRKN, lead to difficulties in the process by which damaged mitochondria are removed from the cell. In 2019, a group led by Richard Youle at the NINDS demonstrated that in mice with mutations in PINK1 and PRKN, inducing mitochondrial damage activated inflammatory molecules. Those animals also lost dopamine-producing neurons in their brains and developed problems with movement — hallmarks of Parkinson’s disease. These effects didn’t occur when the researchers repeated the experiment with mice engineered to lack an important inflammatory molecule. Together, these findings illustrated that in animals genetically predisposed to Parkinson’s, either stress or glitches in mitochondrial DNA could trigger the inflammation that promotes the disease.
Our cells have mechanisms by which to eliminate dysfunctional mitochondria. One key mechanism involves the proteins in PINK1 and Parkin.
Cells have several quality control mechanisms to remove dysfunctional mitochondria. One important mechanism involves the proteins Parkin and PINK1. When a mitochondrion is damaged, PINK1 and Parkin recruit a phagophore, which engulfs the organelle and begins the process of degrading it. When such quality control systems fail, damaged mitochondrial DNA (mtDNA) can escape from the mitochondria. The method by which this happens is still under study. However, once released, mtDNA fragments can activate molecules such as cGas-STING or inflammasomes, both of which sense foreign DNA from viruses and other invaders. This, in turn, can increase the production of cytokines and cause inflammation.
As evidence increases that leaking mitochondrial DNA is harmful, some scientists are beginning to study why. One hypothesis is that the organelle ejects continual, low levels of DNA over time. When exacerbated by environmental or genetic factors, the accumulation may reach the level where diseases happen.
Psychological stress may also be a factor. In a 2019 study, Martin Picard, a mitochondrial psychobiologist at Columbia University, and his colleagues reported that after a brief public-speaking task where participants were asked to defend themselves against an alleged transgression, levels of free-floating mitochondrial DNA in the bloodstream rose, indicating that the mitochondria had expelled their genetic material.
This type of DNA release and mitochondrial damage may contribute to human disease in which inflammation plays a key role, even without an infection, or conditions like autoimmune disorders, cancer, and neurodegenerative disorders.
Other studies are examining whether mitochondria-induced inflammation can increase the process of aging. One report suggested that mice engineered to have unstable mitochondrial DNA aged more quickly than their counterparts, and they developed problems like bone and hair loss more quickly. Eliminating the elements of the immune system activated by mitochondria DNA reversed this process, extending the animals’ lifespans by around 40 days.
Multi-functional mitochondria
Mitochondria play other roles in maintaining healthy brain function. They can also cause problems when dysfunction occurs. For example, mitochondria help control the balance of potentially toxic byproducts of cellular metabolism called reactive oxygen species and the synthesis of stress hormones like cortisol.
In addition, mitochondria are very dynamic. They communicate with each other through physical connections and signaling molecules. They undergo fission, which is when a large mitochondrion splits into 2 smaller ones, or fusion, which is when 2 combine to produce 1. These ongoing dynamics may impact brain function and behavior in ways that scientists are just now discovering.
Carmen Sandi, a behavioral neuroscientist at the Swiss Federal Institute of Technology, and her group have examined mitochondria in mice with high levels of anxiety-like behaviors, such as being less willing to spend time in open areas. They’ve found that in those animals, mitochondria in the neurons of the nucleus accumbens, a brain area involved in processing reward, were less able to produce ATP compared to those found in animals that displayed lower levels of anxiety. The high-anxiety animals also displayed lower levels of an enzyme involved in fusion. Increasing the level of this protein not only restored mitochondrial function but also reduced anxious behaviors, the researchers found.
Studies like these suggest that one day treatment for brain disorders that target these organelles may be found. One clinical trial is underway to examine whether nutrient supplements can reverse the mitochondrial abnormalities that have been identified in children with autism.
Testing these hypotheses takes time. In the meantime, researchers are discovering the many functions that mitochondria have in the brain. The work may be preliminary. But the evidence is gathering from a multitude of disciplines like immunology, neuroscience, and psychiatry. The work is exciting and promises hope to many.