Stressed? Depressed? Anxious? Blame Your Mitochondria

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Your brain is a metabolically fierce organ, punching way above its weight of two pounds to consume 20 to 25 percent of the body’s fuel supply. The brain’s energy-making machinery, centered in mitochondria, is powering your ability to see this page, decode the symbols, take in the information, and maybe even store some of it in memory. Given the outsize energy demands of the brain, it is intensely populated with mitochondria, likely thousands of them per neuron. The evidence is accumulating that the many ways they function, and the many possibilities for dysfunction, are the common source of all mental health disorders.

Descendants of an ancient bacterium that made its way into an equally ancient single-cell organism and worked out a cooperative living agreement—an event that likely happened two billion years ago—mitochondria are essential for producing energy, although that is by no means all they do. The energy mitochondria produce not only sustains life but enables adaptation to challenges. Mitochondria respond very quickly to your needs: They’re there for your muscles when you climb a hill or ride a bike. You can’t make a decision, answer a question, or laugh at a punch line without a blast of energy in your brain. The sensitivity of mitochondria to environmental needs makes them a critical nexus for our adaptation to the ever-changing demands of the inner and outer environment.

That same sensitivity also may make them especially vulnerable to assault from an array of environmental perturbations. That vulnerability is what makes mitochondrial dysfunction a prime contender as the source of psychiatric disorders.

As the descendants of once-independent organisms, mitochondria retain some autonomy; for example, they have their own DNA, something that helps mitochondria respond quickly to local energy demands without having to first consult the nuclear DNA. It also allows mitochondria to multiply on their own.

Unprotected by telomeres, mitochondrial DNA is especially vulnerable to damage, which can significantly affect energy production capacity. And because of the outsize importance of mitochondria to brain activity, even small changes in mitochondrial function can have big effects. Research increasingly ties mitochondria dysfunction to a wide range of mental health conditions, from developmental disorders such as autism to psychiatric ills such as depression, bipolar disorder, and schizophrenia, to neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases.

Mitochondria as the Master Regulator

Beyond energy production, mitochondria play an essential role in the production and regulation of neurotransmitters, including serotonin, dopamine, and that all-purpose brake on neural excitability, GABA. Mitochondria are key regulators of hormones, including cortisol, essential to the stress response, and the hormones of reproduction: estrogen, testosterone, and progesterone.

Mitochondria are epigenetic forces, regulating the expression of cellular genes, turning them on and off. They appear to be the ultimate responders to adversity. Everything they do has a profound impact on cognition and all other mental processes. Many roads point to mitochondria as the hub of what goes wrong in psychiatric and neurodegenerative disorders.

What Goes Wrong

There are many ways the function of mitochondria can be impaired. A major one is oxidative stress. ATP, derived from the breakdown of glucose, is the molecule that mitochondria produce for power, drawing on the energy contained in its chemical bonds. In the constant production of ATP, some electrons go rogue and create free radicals of oxygen, also called reactive oxygen species, (ROS). Free radicals can damage DNA, proteins, and other important cellular components. Oxidative stress describes the condition within cells when the free radicals of oxygen released in ordinary activity outnumber the antioxidants available to neutralize them and protect against the damage they can do. Because it is so metabolically active consuming so much oxygen for its constant activity, the brain is particularly susceptible to oxidative stress. In fact, the relentless accumulation of oxidative stress in all cells is why we age. Prolonged oxidative stress erodes the efficiency and activity of mitochondria, and it can damage mitochondrial genes.

Another pathway to problems is poor garbage removal. All cells engage in a process of self-maintenance and self-renewal, called autophagy, by which worn-out or damaged parts are broken down and removed, and reusable elements are upcycled into new cells. Autophagy keeps cells in working order. Mitophagy is the process of upkeep and rejuvenation of mitochondria, and, given the demands on mitochondria, meticulous housekeeping is essential to the viability and function of their host brain cells.

Mitochondria are normally capable of swiftly meeting energy demands by increasing their number, a process called mitochondrial biogenesis. A change in biogenesis can also impair mitochondrial function.

Mitochondrial dysfunction from any cause not only leads to a decrease in ATP levels and energy production and an increase in the generation of ROS but it can also lead to inflammation. If, because of reduced mitochondrial function, defective mitochondria are not removed by mitophagy, they can release their contents, setting off inflammatory processes.

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Fatigue, Worry, and More When Mitochondria Malfunction

The malfunction of mitochondria leads to a lack of brain energy that affects every aspect of brain operations. It is a source of fatigue. It is a cause of all degrees of cognitive sluggishness and impairment; it undermines cognitive flexibility, by which we adapt to life’s ever-changing circumstances. It impedes the most energy-intensive of operations, executive function, affecting everything from attentional focus and decision-making to impulse control, emotion regulation, and memory. Those negative thoughts and worries that play on repeat in our head? It takes lots of mental energy to keep them from taking over.

Imaging studies of the brain, such as functional magnetic resonance imaging (fMRI), are essentially studies of brain metabolism. They measure changes in cerebral blood flow to meet the demands of neural activity. The last few decades have provided overwhelming evidence that in every mental disorder, there are disturbances in cerebral blood flow that show up on imaging studies; that is, there are irregularities of brain metabolism, which is centered in mitochondria. In some cases, specific brain regions are overactive, in others some regions are underactive. In all cases, mitochondria are implicated.

A Link to Insulin

There is more evidence that malfunctioning mitochondria cause mental illness. Metabolic disorders such as obesity and cardiac disease are extremely common in the U.S. According to the Centers for Disease Control and Prevention, more than 40 percent of U.S. adults are obese. And more than 35 percent have anxiety, depression, or both. The incidence of mental disorders among those with metabolic disorders is two to three times greater than normal. Those with mental disorders have two to three times greater chances of developing obesity and diabetes. Both kinds of disorders share a common cause: impaired mitochondrial function.

Obesity, for example, is commonly accompanied by insulin resistance. Insulin is an important regulator of metabolism as well as a signaling molecule: Insulin resistance not only influences glucose metabolism and energy production but also, for example, alters dopamine dynamics, affecting reward and motivational networks in the brain, and is linked to both anxiety and depression.

The evidence is mounting that mental illness is, first and foremost, a consequence of metabolic malfunction. That same knowledge is also paving the way for a whole new approach to treating mental distress.