Inow return to the discussion of metabolism in order to continue to put the pieces of the puzzle together. Recall the traffic analogy from Chapter Five where each car was like a human cell. I described metabolism as very complicated. It’s constantly changing, and may be different in different cells at different times. To be fair, that isn’t really one common pathway. It’s more like hundreds of different metabolic pathways.
But what controls metabolism? How do food and oxygen know where to go? What changes the metabolic rate in various cells? What makes some cells slow down, while others go faster? What is driving this intricate network of the human body?
Some would say it’s the brain. Although the brain plays a critical role in metabolism, it can’t control metabolism in all the different cells of the body at the correct times. Like city traffic, there must be some degree of control at the level of each car, or in the case of the human body, at the level of each cell. Cells receive input from other cells telling them to stop or go. Cells in close proximity also have signals that make neighboring cells stop or go (think brake lights on a car). But some of the signals are sent all over the body. They might originate in a brain cell or a liver cell, but they then travel long distances to affect cells throughout the body. These processes all lead to a coordination of metabolism, just like city traffic is coordinated on many levels, too.
There are many things that make city traffic flow. The different types of roads and highways. The different speed limits on different roads. The stop signs and stoplights. These are all important to the organization and flow of city traffic. But in the end, the true and primary force controlling the flow of traffic boils down to the drivers in the cars. They know the rules and they follow them. They make the cars go. They make the cars stop. They use turn signals. They look out for trouble. They steer the cars around problems. They drive the cars to their destinations. And even though the drivers don’t know what’s happening with all the other cars on all the other roads or highways, everything works.
Do human cells have “drivers” making the cells stop and go? It turns out that they do. The drivers of human cells, and human metabolism, are called mitochondria. And they are the common pathway to mental and metabolic disorders.
If you’ve ever taken a biology course, you likely remember that mitochondria are the “powerhouses of the cell.” Mitochondria make energy for cells by turning food and oxygen into ATP. While there’s no question that their role in energy production is critical, mitochondria are so much more than powerhouses. Without them, life as we know it wouldn’t exist.
In the 2005 book Power, Sex, Suicide: Mitochondria and the Meaning of Life, Dr. Nick Lane provides a thorough and compelling story of mitochondria and their role in human evolution.1 Although the title might suggest a pop culture quick read, Lane provides a rigorous scientific history of mitochondria and their role in human health and life itself.
Mitochondrial Origins
Once upon a time, the first mitochondrion (mitochondria is the plural of a single mitochondrion) was a bacterium. Researchers estimate mitochondria evolved from an independent living organism sometime between one and four billion years ago. A 1998 paper published in Nature suggests they share many genes with the modern-day Rickettsia prowazekii, a bacterium that causes typhus.2 Billions of years ago, another single-cell organism, an archaea, engulfed this ancestral mitochondrion. Instead of the mitochondrion dying after being engulfed, as usually happens, they both lived. This new organism is thought to have evolved into the first eukaryotic cell (a cell with a nucleus). The inside bacterium began to focus on making energy, and the outside organism could focus on getting food. Make no mistake—this is important. It is not a trivial fact.
Thus, before there was a cell nucleus housing human DNA, and before there were other organelles, there was a mitochondrion—a single mitochondrion and a single host cell. Together, they were determined to survive. Actually, not just survive, but thrive. Like all forms of life—they were in it to win it. And win it they did!
Over time, it was this symbiotic arrangement that allowed for multicellular life—essentially all life that we can see with our eyes today. In all eukaryotes, these internal bacteria evolved into mitochondria. In plants and algae (also eukaryotes), some of them also evolved into what we now call chloroplasts. Although mitochondria and chloroplasts have different names, they look and function similarly, and they are thought to be descended from the same bacterium from billions of years ago. Furthermore, it’s believed that this merger happened only once, and that all plants, animals, algae, and fungi that exist today descended from this same organism. For those who believe in God, this concept of a single event starting life as we know it might be reassuring. For those who don’t believe in God, it was just one of those unusual and unlikely events that shaped evolution for billions of years to come. Regardless of what you believe, it was an important event in the story of life.
In evolution, being first matters. For example, when genes overlap among different organisms, they are usually believed to be more important than genes that are unique to specific species. The unique genes are thought to have occurred more recently in the evolutionary timeline, while the common genes developed much earlier. Things that have persisted for a long time are thought to be more essential to life. There are at least two reasons for this. The first is that evolution tends to get rid of things that are not essential or don’t confer some advantage in terms of survival or reproduction. If organisms evolve to no longer need a trait, it will no longer be selected for and will often eventually disappear. The second is that new genes and traits must develop with and adapt to the genes and traits that are already there. Mitochondria were in eukaryotic cells first. Initially, it was just a single bacterium and a single outside cell. Over time, the nucleus and other organelles developed. As important as these other organelles are, mitochondria were there first. They likely influenced the development of these other cell parts and became indispensable. In fact, these other cell parts don’t work correctly without mitochondria.
Modern Mitochondria
Mitochondria are no longer able to replicate themselves outside of a eukaryotic cell. In humans, mitochondria transferred most of their DNA to the cell’s nucleus, where human DNA resides. There are about 1,500 mitochondrial genes that are now embedded within human DNA. These 1,500 genes make proteins that are required to either create or maintain mitochondria, and these proteins are shared with all the mitochondria in the cell. However, mitochondria didn’t give up all their DNA. Each one of them still has thirty-seven genes. Individual mitochondria can use that DNA on their own—and thus mitochondria maintain some degree of independence, both from each other and from the cell in which they reside. This is highly unusual in biology, and its purpose is the subject of debate. The point, however, is this: Mitochondria and human cells are now 100 percent committed to each other. Neither can survive without the other.
Mitochondria are tiny. On average, each human cell has about three to four hundred mitochondria.3 This means that there are about ten million billion mitochondria in the human body. They make up about 10 percent of our body weight despite their tiny size. In metabolically demanding cells—such as brain cells—a single cell can contain thousands of mitochondria, with mitochondria making up 40-plus percent of the cell volume.
Mitochondria are busy. Although small amounts of ATP can be produced without mitochondria through a process called glycolysis, mitochondria produce the lion’s share of ATP, especially for brain cells. In the average human adult, they make about 9 × 1020 ATP molecules every second.4 One group of researchers looked at brain cells using specialized imaging techniques and found that a single neuron in the human brain uses about 4.7 billion ATP molecules every second.5 That’s a lot of ATP!
Mitochondria move. This is a fairly recent discovery based on new techniques for studying living cells.6 When a cell is dead under the microscope, nothing moves, so it’s easy to see why researchers didn’t think that mitochondria would be mobile. Other organelles typically are not. The finding that mitochondria actually move around living cells was highly unexpected. If you’d like to see a video of mitochondria moving, you can see them in the PLOS Biology article in the endnotes.7 There are many other videos available online. There is a network of microtubules and filaments throughout the cell, often referred to as the cytoskeleton, that mitochondria use for their movement. There are many mechanisms involved, which are beyond our scope, but the point is simple—some mitochondria move around.8 However, it appears that not all mitochondria are moving. Some stay in one place, while others move.
Why are they moving? Well, one reason is that they appear to go to the places in the cell where things are happening and where energy is needed. Energy needs to be produced in the right amount, in the right place, at the right time, and it goes through an unimaginably fast recycling process that involves mitochondria. The mitochondria that aren’t moving appear to stay in places where things are always happening—either near factories where proteins are made (ribosomes) or synapses where there is a lot of activity, which is a very important fact relevant to how the brain functions. Researchers looking at brain cells under microscopes have known for decades how to identify where the synapses are—they look for the mitochondria.
Mitochondria are rapid recyclers. ATP is the energy currency of human cells. When it is used as energy, a phosphate group is removed, which turns it into adenosine diphosphate, or ADP. This ADP can’t supply much energy anymore, but if a phosphate group is added back to it, it’s as good as new. That’s what mitochondria do. They take ADP and turn it back into ATP by attaching a phosphate group, then transfer it out to the cell cytoplasm where it is needed. They give one ATP and recycle one ADP simultaneously. If there is a lot of activity in a particular part of the cell, you will find mitochondria there. They have to provide the ATP, but they also suck up all of the ADP and recycle it. You can think about mitochondria as little vacuum cleaners, going around the cell and sucking up ADP and churning out ATP.
Remember that I said there were billions of ATP molecules being used every second in just one brain cell? Well, if there isn’t a mitochondrion or two (well . . . maybe more than that) in the right place at the right time to both deliver all that ATP and recycle all the ADP, things will back up quickly and either slow down or stop working.
However, mitochondrial movement is more important than just making sure enough energy is supplied in the right place at the right time. It’s also related to mitochondrial interactions with other organelles and with each other. These interactions are critically important to almost all cell functions and even gene expression.
To demonstrate the role of mitochondria, I’ll first need to review some basic information on how neurons work. Although the function of any cell is complicated, and brain cells even more so, there are some basics that are directly regulated by mitochondria. Better understanding them will allow me to tie metabolism and mitochondria to distinct functions of brain cells. I’ll use the next chapter to explain how all the symptoms of mental illness are directly related to mitochondria and metabolism.
Neurons have a resting membrane potential. Basically, this means that the inside of the cell has a negative charge compared to the outside of the cell. This charge is critically important to the function of the cell. It is created by ion pumps, which pump sodium, potassium, calcium, and other ions either inside or outside of the cell, or between compartments within the cell. These pumps all require energy.
Cells do a lot of ion pumping in order to set themselves up to be ready to fire. When the cell is triggered, it sets off a cascade of events that results in the cell doing its thing, whether that entails releasing a neurotransmitter or a hormone, or doing something else. It’s like setting up a row of dominoes. It takes time and work to set them up, but it’s easy to push them all over by simply nudging one of them. Once they all fall down, they need to be set up again. That requires more work. Mitochondria provide almost all the energy needed to do all of this.
What Else Do Mitochondria Do?
Calcium levels play an important role in the function of cells. High levels of calcium in the cytoplasm can trigger all sorts of things to happen. In many ways, calcium is an “on/off” switch. When levels are high, the cell is “on.” When levels are low, the cell gets turned “off.” Mitochondria are directly involved in calcium regulation. When mitochondria are prevented from functioning properly, calcium regulation is disrupted—and this important “off” switch can be as well.9 Therefore, mitochondria are essential in turning cells both on and off. They provide the energy needed for ion pumping, and they also regulate the calcium levels that function as essential on/off signals.
Energy and mitochondria are required to turn cells both on and off. This may seem paradoxical, but it will make more sense if you think of the “off” switch as electronic brakes on a car that require energy to work. Without enough energy to apply the brakes fully and quickly at appropriate times, the car can become impossible to control and cause major disruptions in the flow of traffic. These dichotomous consequences of metabolic and mitochondrial dysfunction are important to understand. Some cells will stay on too long when they are energy deprived, while other cells will fail to work. I will come back to this soon enough.
Turning cells on and off is critically important. Understanding this function will help us explain most of the symptoms of mental illness. However, mitochondria actually do much more than that. Their role in human health is a cutting-edge, vigorous area of research that spans almost every field in medicine.
Let’s outline some of the other roles that mitochondria play that are important to their relationship with mental health.
Mitochondria Help Regulate Metabolism Broadly
In 2001, a peptide called humanin was first reported to have broad effects on metabolism and health.10 The gene for this peptide appears to reside on both mitochondrial DNA and nuclear DNA. It was first discovered in research on Alzheimer’s disease. Since its discovery, two other peptides, MOTS-c and SHLP1–6, have been discovered and added to a new class of molecules called mitochondrially derived peptides. The genes for these peptides are on mitochondrial DNA, and these peptides are produced by mitochondria. They are now of great interest to researchers. They have been shown to have beneficial effects on illnesses such as Alzheimer’s disease, strokes, diabetes, heart attacks, and certain types of cancer. They also have broad effects on metabolism, cell survival, and inflammation.11 The existence of these peptides suggests that mitochondria are able to communicate with each other through these peptide signals in order to regulate metabolism throughout the body.
Mitochondria Help Produce and Regulate Neurotransmitters
Neurotransmitters have been a primary focus in the mental health field. It turns out that mitochondria play critical roles in their production, secretion, and overall regulation.
Neurons often have one specific neurotransmitter that they specialize in making. Some make serotonin. Others make dopamine. The process of making a neurotransmitter takes energy and building blocks. Mitochondria provide both. They play a direct role in the production of acetylcholine, glutamate, norepinephrine, dopamine, GABA, and serotonin.12 Once made, neurotransmitters are stored in vesicles, or little bubbles, until they are ready to use. Vesicles filled with neurotransmitters travel down the axon to get to their ultimate release site. That takes energy. The signal to release neurotransmitters depends upon the resting membrane potential and calcium levels that I discussed. Once that signal comes, the actual release of neurotransmitters also takes energy. Fascinatingly, once neurotransmitters are released at one location, the mitochondria move to another location of the cell membrane to release a new batch of neurotransmitters.13 Once released, neurotransmitters have their effect on the target tissue, whether it’s another nerve, muscle, or gland cell. After they are released from the receptors on the target cell, they are sucked back into the axon terminals (a process called reuptake), and you guessed it, that takes energy. They are then repackaged back into vesicles for the next round—yet more energy.
Mitochondria are normally found in large supply at synapses. When they are prevented from getting to the synapses, neurotransmitters don’t get released, even if there is ATP present.14 When mitochondria aren’t functioning properly, neurotransmitters can become imbalanced. Given that neurotransmitters are an important way for nerve cells to communicate with each other, imbalances can disrupt normal brain functions.
The role of mitochondria in regulating neurotransmitters goes much further than just their involvement in synthesis, release, and reuptake. Mitochondria actually have receptors for some neurotransmitters, indicating a feedback cycle between neurotransmitters and mitochondria. They also have some of the enzymes involved in the breakdown of neurotransmitters, such as monoamine oxidase. They are involved in regulating the release of GABA, and they actually store GABA within themselves.15 Finally, several neurotransmitters are known to regulate mitochondrial function, production, and growth. Clearly, neurotransmitters are much more than just messengers between cells impacting mood. They are essential regulators of metabolism and mitochondria themselves. I’ll come back to this later.
Mitochondria Help Regulate Immune System Function
Mitochondria also play an essential role in immune system function.16 This includes fighting off viruses and bacteria, but it also includes low-grade inflammation, something that has been found in most metabolic and mental disorders to some degree. Mitochondria help regulate how immune cells engage with immune receptors. When cells are highly stressed, they often release components of mitochondria, which serve as a danger signal to the rest of the body, one that activates chronic, low-grade inflammation.17
One study looked at specific types of immune cells called macrophages to see how these cells coordinate the complicated repair processes in wound healing. The cells do different things during different phases of healing. Up until this study, it wasn’t known how the cells know when and how to change between phases. The researchers found that mitochondria specifically controlled these processes.18
Mitochondria Help Regulate Stress Responses
We now know that mitochondria help control and coordinate the stress response in the human body. This includes both physical and mental stressors. Physical stressors include things like starvation, infection, or a lack of oxygen. Mental stressors are anything that threatens or challenges us (as talked about in the previous chapter).
When cells are physically stressed, they initiate a process called the integrated stress response. This is a coordinated effort by the cell to adapt to and survive adverse circumstances through changes in metabolism, gene expression, and other adaptations. Many lines of research show that mitochondrial stress itself leads to the integrated stress response.19 If the cell isn’t able to manage the stress, one of two things happens—it either triggers its own death, a process called apoptosis, or it enters into a “zombielike” state called senescence, which has been associated with aging and many health problems, such as cancer.
Up until recently, it wasn’t known how the different aspects of the psychological stress response are all coordinated in the body and brain. It turns out that mitochondria play a critically important role! One brilliant study by Dr. Martin Picard and colleagues demonstrated this, and its title says it all: “Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress.”20 These researchers were studying mice and genetically manipulated their mitochondria to see what effects these manipulations had on the stress response. They manipulated only four different genes—two located in mitochondria themselves and two located in the cell nucleus that code for proteins used exclusively in mitochondria. Each genetic manipulation resulted in different problems with mitochondrial function. However, even with only four manipulations, they found that all the stress response factors were affected. This included changes in cortisol levels, the sympathetic nervous system, adrenaline levels, inflammation, markers of metabolism, and gene expression in the hippocampus. Their conclusion was that mitochondria are directly involved in controlling all these stress responses, and if mitochondria aren’t functioning properly, these stress responses are altered.
Mitochondria Are Involved in Making, Releasing, and Responding to Hormones
Mitochondria are key regulators of hormones. Cells that make hormones require more energy than most. They synthesize the hormones, package them up, and release them, just as I described for neurotransmitters. It takes a lot of ATP to do this, and mitochondria are there to deliver it.
For some hormones, mitochondria are even more important—this includes well-known names like cortisol, estrogen, and testosterone. The enzymes required for initiating the production of these hormones are found only in mitochondria. Without mitochondria, these hormones aren’t made. But there’s more. Mitochondria in other cells sometimes have receptors for these hormones. So, in some cases, these hormones can begin in mitochondria in one type of cell and end with mitochondria in another type of cell.
Mitochondria Create Reactive Oxygen Species (ROS) and Help Clean It Up
Mitochondria burn fuel—either carbohydrates, fats, or protein. Burning fuel can sometimes create waste products. When mitochondria burn fuel, electrons flow along the electron transport chain. These electrons are a source of energy usually used to make either ATP or heat. However, sometimes these electrons leak outside of the usual system. When they do, they form what are called reactive oxygen species (ROS).21 These include molecules such as superoxide anion (O2-), hydrogen peroxide (H2O2), hydroxyl radical (•OH), and organic peroxides. At one point, researchers believed ROS were simply toxic waste products. We now know small amounts of ROS actually serve a useful signaling process inside the cell. For example, a 2016 paper published in Nature found that ROS were the primary regulators of heat production and energy expenditure—a broad measure of metabolic rate.22 However, large amounts of ROS are toxic and result in inflammation.23 You may have heard the term oxidative stress—that’s what this is! ROS are known to cause damage to mitochondria and cells. They are associated with aging and many diseases. Given that ROS are produced right in the mitochondria and are highly reactive, they often damage mitochondria first. The mitochondrial DNA is unprotected, so large amounts of ROS are known to result in mitochondrial DNA mutations. These ROS can also damage the mitochondrial machinery itself. If they leak outside of the mitochondria, they can damage many different parts of the cell.
Additionally, mitochondria serve as ROS janitors. As well as producing ROS, mitochondria also clean up some of it up through an elaborate system of enzymes and other factors that serve to detoxify ROS.24 Cells have other antioxidant systems, too, but mitochondria play a role. When this detoxification system fails, these ROS waste products can pile up and cause damage. This can lead to cellular dysfunction, otherwise known as aging, cell death, and disease.
Mitochondria Are Shape-Shifters
Mitochondria change shape in response to different environmental factors. Sometimes they are long and thin. Other times they are short and fat. Sometimes they are round. In addition to changing shape, they interact with each other in profound ways. They can merge to make just one mitochondrion—a process called fusion. They can divide and form two mitochondria—a process called fission. These changes in shape are very important to cell function. In 2013, two articles published in the journal Cell showed that the process of mitochondria fusing with each other significantly impacts fat storage, eating behaviors, and obesity.25 Mitochondrial changes in shape and their fusion with each other appear to create signals that can affect the entire human body. When mitochondria are prevented from doing these things, metabolic problems ensue, not just in the cells affected, but sometimes throughout the body.
Mitochondria Play a Primary Role in Gene Expression
Nuclear DNA is where the human genome resides. It’s contained within the cell nucleus. Researchers once thought that genes controlled everything about the human body. They assumed that the nucleus was the control center of the cell. We now know that it’s not always about the genes themselves, but more about what causes certain genes to turn on or off. This is the field of epigenetics.
Mitochondria are primary regulators of epigenetics. They send signals to the nuclear DNA in several different ways. This is sometimes referred to as the retrograde response.
It has long been known that the ratio of ATP to ADP, levels of ROS, and calcium levels can all affect gene expression. As you now know, these are all directly related to mitochondrial function. However, given that these are also markers of general cellular health and function, no one thought too much of it. They certainly didn’t think of it as a way for mitochondria to directly control the expression of genes in the nucleus.
In 2002, it was discovered that mitochondria are required for the transport of an important epigenetic factor, nuclear protein histone H1.26 This protein helps regulate gene expression and is transported from the cytoplasm to the nucleus, a process that requires ATP. Researchers discovered, however, that ATP alone isn’t enough. Mitochondria must be present in order for this transfer to occur. Without mitochondria, this transfer doesn’t happen.
In 2013, it was discovered that mitochondrial ROS directly inactivate an enzyme called histone demethylase Rph1p, which regulates epigenetic gene expression in the cell nucleus.27 This process was found to play a role in extending lifespan in yeast and is thought to possibly play a role in humans as well.
In 2018, two additional studies demonstrated even more of a role for mitochondria in gene expression. The first was a report by molecular biologist Maria Dafne Cardamone and colleagues showing that a protein, GPS2, is released by mitochondria in response to metabolic stress.28 Metabolic stress can be caused by a lot of different things, but starvation is a clear example. After GPS2 is released by mitochondria, it enters the cell nucleus and regulates a number of genes related to mitochondrial biogenesis and metabolic stress.
Another group of researchers, Dr. Kyung Hwa Kim and colleagues, found another mitochondrial protein, MOTS-c, that is coded for by mitochondrial DNA and plays a role in gene expression.29 This was very unexpected. Up until about twenty years ago, everyone assumed that mitochondrial DNA was just about machinery needed for ATP production. MOTS-c gets produced in response to metabolic stress as well. After MOTS-c is produced in the mitochondria, it makes its way into the nucleus and binds to the nuclear DNA. This results in the regulation of a broad range of genes—ones related to stress responses, metabolism, and antioxidant effects.
Finally, and most spectacularly, Dr. Martin Picard and colleagues experimentally manipulated the number of mitochondria with mutations in cells and found that as they increased the number of dysfunctional mitochondria, more epigenetic problems and changes occurred.30 The impact was on almost all of the genes expressed in the cells. Ultimately, in situations in which almost all the mitochondria were dysfunctional, the cells died. This study provided evidence that mitochondria are not just involved in the expression of genes related to energy metabolism, but possibly in the expression of all genes.
Mitochondria Can Multiply
Under the right circumstances, cells will make more mitochondria—a process called mitochondrial biogenesis. Some cells end up with a lot of mitochondria. These cells can produce more energy and function at a higher capacity. It is widely believed that the greater the number of healthy mitochondria in a cell, the healthier the cell. We know that the number of mitochondria decreases with age. We also know that the number of mitochondria decreases with many diseases. People who are considered the “fittest” among us—athletic champions—have more mitochondria than most, and their mitochondria appear to be healthier.
Mitochondria Are Involved in Cell Growth and Differentiation
Cell growth and differentiation is a complicated process during which a generic stem cell becomes a specialized cell. Differentiation means that the cells become different from each other and take on specialized roles. Some become heart cells. Others become brain cells. Within the brain, different cells take on varying roles. Brain cells change throughout life. Some form new synapses. Some prune unnecessary parts. Some grow and expand when needed. This is neuroplasticity.
This process of growth and differentiation involves activation of specific genes in the right cells at the right times. It also involves many signaling pathways. Lastly, it involves the production of building blocks for new cells and new cell parts, balanced with energy needs.
It has long been known that mitochondria are essential to cell growth and differentiation. Most researchers assumed it was simply a matter of their powerhouse function since cell growth and differentiation require energy. Recent research, however, strongly suggests a much more active role. Their regulation of calcium levels and other signaling pathways are essential to this process.31 Their fusion with each other appears to send signals that activate genes in the nucleus. When mitochondria are prevented from fusing with each other, the cells don’t develop correctly.32 Other research has shown that mitochondrial growth and maturation is essential to proper cell differentiation.33 Still other research has shown a direct and essential role of mitochondria in the development of brain cells.34 The bottom line is that cells don’t develop normally when mitochondria aren’t functioning properly.
Mitochondria Help Maintain Existing Cells
In the previous chapter, I discussed autophagy and cell maintenance. It turns out that mitochondria are directly involved in this process, too. They generate many of the signals, such as ROS and other metabolic factors, that play a key role in autophagy. They also interact with other parts of the cell, such as lysosomes, that are involved in the process. Maintenance work takes energy and building blocks as well, and mitochondria are there to provide both.
Mitochondria appear to be in a complicated feedback cycle with autophagy, as dysfunctional mitochondria can be removed and replaced with healthy mitochondria in a process known as mitophagy. Mitochondria can be beneficiaries of autophagy, but they also play a role in stimulating autophagy more broadly for the entire cell.35
Mitochondria Eliminate Old and Damaged Cells
Cells die every day. There are two well-known types of cell death—necrosis and apoptosis. Necrosis occurs when a cell is abruptly killed, such as a heart cell dying during a heart attack. Necrosis is a bad thing. Apoptosis occurs when cells get old or damaged. Apoptosis is a planned process often referred to as programmed cell death—the signal to die actually comes from the cell itself. Overall, apoptosis is seen as an extraordinarily good thing for human health and survival. It allows old cells to be replaced by new ones. It eliminates damaged cells that might turn into cancer. Every day, about ten billion cells in the human body die and are replaced by new ones.36
It was once thought that genes in the nucleus controlled apoptosis. We now know that’s not true. It’s mitochondria. When mitochondria experience high levels of stress and accumulate large amounts of ROS, they begin to degrade. When this happens, they release a protein called cytochrome c, which then activates what are called “killing enzymes”—the caspases. These enzymes degrade everything in the cell until it dies. Many of the cell parts get recycled.
Autophagy and apoptosis are somewhat related, but they are different processes. Autophagy is usually about repairing and replacing parts within a cell, but the cell usually remains alive. Apoptosis is the death of an entire cell. Nonetheless, they are both required for health and longevity, and mitochondria play a role in both.
There are even more types of cell death, beyond the scope of this book. Nonetheless, one review was able to link all of them to the functions of mitochondria.37
Putting It All Together
Change is hard. Models, practices, and conceptual frameworks are difficult to shift. But what if our ideas about the control of cells have been all wrong?
If we go back to our automotive analogy, I suggested that each cell was like a car in the congested traffic of a large city. If we look inside that car, there are many drivers—all the mitochondria. It might be easier to change the metaphor at this level and think of the inside of each cell as a factory. The factory receives supplies, such as glucose, amino acids, and oxygen, and performs a function. Some make neurotransmitters. Others make hormones. Some are muscle cells and cause the body to move. Mitochondria are the workers inside those factories (mitochondria as workers is an analogy Nick Lane used in his book as well).38 There are many different roles and tasks for them. Some mitochondria help with the production and release of hormones or neurotransmitters. Others serve as janitors—helping to clean up ROS and other debris. Some help communicate with the nucleus—sending signals to turn genes on or off. They are the regulators of calcium, ROS, and other important signals in cells. They work together and communicate with each other—they fuse with each other, move around cells, and communicate with mitochondria in other cells through hormones, such as cortisol, and through other mechanisms, such as mitochondrially derived peptides. And of course, they provide most of the power—or ATP—to make the factory work. When workers in one cell aren’t doing well, they not only affect the rest of the workforce in that cell, but they can also affect the workers in other cells.
Over the past twenty years, a lot of the new evidence on the role of mitochondria in the cell has been shocking and unexpected. Almost no one thought that mitochondria could control the regulation of genes in the nucleus—both on a daily basis and during cell growth and differentiation. Their interaction with and regulation of other organelles, such as the endoplasmic reticulum and lysosomes, were also surprising. They were usually thought of as relatively insignificant, and very small, ATP factories. They were sometimes described as “little batteries.” Many researchers still see them this way.
For centuries, researchers have been trying to figure out how cells work. Up until recently, they have focused primarily on all the big parts of cells and largely ignored the tiny little mitochondria. Many still think the nucleus, with its coveted human genome, is the control center. Others think that it’s all about the outside cell membrane and the different receptors that are embedded into it. Different neurotransmitters or hormones make cells do things. What if both takes have some truth in them, but the real story is about the mitochondria—the workers? Given all the roles that mitochondria play in so many different aspects of cell function, is it possible that they are the real answer to understanding how cells work? What if all the different organelles in a cell are just big machines or storage sites to be used by mitochondria to do different tasks in a cell? Could the nucleus simply be a large storage center for the DNA, the blueprints of the cell, to be used when called for by the mitochondria? Could the other organelles be large machines, ones that make proteins (ribosomes) or waste disposal machines (lysosomes), to be used by the mitochondria for these different purposes? After all, mitochondria are the only organelles that move around the cell, interact with each other, and interact with all the other organelles. Mitochondria were in the cell first. They were the first organelle. They were also an independent living organism at one point. In many ways, the evidence can’t rule this out.
To be clear, I’m not suggesting that mitochondria have brains and make independent decisions on all of these functions. Instead, I am suggesting that they are like little robotic workers, doing what they are programmed to do. They are longtime, loyal servants to human cells. But like so many unappreciated servants and workers, maybe they deserve a little more respect and recognition for all that they do.
Whether you like this analogy or not, even if you want to continue to think of mitochondria as nothing more than little batteries, one thing is abundantly clear and uncontroversial—when mitochondria aren’t working, neither is the human body or brain.