Mitochondria — A Series On Improvement — Part I
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Part I: What Are Those Things and Why Should I Care?
Updated on: myprotons.com
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Mighty Mitochondria: An Introduction
Mitochondria, which we all know from high school biology as the “power house” of the cell, are little batteries that convert food stuffs and oxygen to energy (ATP) that we use to move, think, and write blogs. In fact, the oxygen you are breathing right now is being sent directly to these little guys and the CO2 that you exhale is a byproduct from their fantastic process of making energy.
These guys weren’t always in our cells hanging out. Billions of years ago an archaea and a bacteria joined at just the opportune moment; a tiny window in time that had a seemingly greater chance of it not happening than happening. Eventually this led to the formation of eukaryotes (multicellular life forms where each cell contains a nucleus and that make up complex organisms such as ourselves). The bacteria in that relationship is now the mighty mitochondria that powers our every move and as we shall see later, they also have control over life and death itself.
The mitochondria actually have their own DNA (mtDNA) which is circular and has multiple copies available, like bacterial DNA. Humans and other eukaryotes have linear DNA and only two copies of each gene. Similar to bacteria, mitochondria can trade genes with one another if one gene becomes damaged. Bacteria can pass genes between them in a given population, so if one bacterium has a gene proven to be useful it is shared with the colony and spreads throughout, which is how antibiotic resistance occurs. This process is called lateral gene transfer. In the mitochondria, the mtDNA has 37 genes total. Of those 37, 13 genes code for 13 critical subunits of the Electron Transport Chain (more on that later). Just to give a comparison in size; the human genome has about 22,000 genes. Over the many years during the early evolution of the eukaryotic cell, the rest of the mitochondrial genes have sought out the bomb shelter of which is of course, the nucleus of the cell. Why after millions of years have the mitochondria held onto these 37 genes of which 13 are critical and sent the rest to the nucleus is something we will discuss later.
As nature is commonly known as “mother nature” the mitochondria are inherited from the maternal line and rarely ever from the paternal. So, the mitochondria zooming around in your cells right now were inherited from your mother. You can either thank her later or have a heated discussion. A mitochondrion can also fuse with another and divide into two mitochondria, during fusion is when they trade genes/repair damage and during fission (division) is when the dysfunctional ones are culled out; a process called mytophagy. The increase in mitochondrial mass is called mitochondrial biogenesis. These guys are always forming vast networks around the cell, changing shape and size. (Exercise and a whole slew of other tricks have been shown to increase mitochondrial biogenesis.) Why would you want more mitochondria? We will get to the answer of this question shortly.
Without mitochondria or something like it, multi-cellular life would not exist as we know it today and the same could be said about life on other planets. Life would have never made it past the primordial slime ball because of the energy requirements for complex multicellular life with larger genomes. Bacteria never evolved beyond bacteria because they have become energetically efficient and do not have enough energy to maintain a larger genome and reproduce quickly, keeping their complexity limited. Larger genomes take longer to replicate during division and require more energy. It’s a matter of dividing faster than your neighbor in the bacterial world. A large genome would put a damper on survival of a given species of bacteria. Like bacteria, mitochondria are small. Mitochondria are now confined inside our cells and can no longer survive outside them as they once did. The number of mitochondria per cell varies. Some of our cells have only a few mitochondria and others have thousands. Cells in the brain and heart for instance, have thousands due to the high metabolic demand of these tissues. These tiny creatures live symbiotically with our cells. They give us energy (ATP) to carry out daily processes and we give them food stuffs and oxygen. It seems to be a pretty solid trade off, but who is the master and who is the slave?
The Samurai in the Cell
These tiny mobile batteries are not so tiny in deed, they are in fact very mighty. Mitochondria can cause what is called Apoptosis, or programed cell death. When the conditions are right, a ballet is preformed and certain biochemical responses are triggered and the outer membrane becomes more permeable due to a burst of free radicals and the mitochondria releases Cytochrome C (located in the Electron Transport Chain) causing the sward to be raised and ready to be brought down on the cell for the greater good of the organism. Cytochrome C is part of the Electron Transport Chain which shuttles electrons down a chain of complexes to generate ATP. Cytochrome C is the literal line between life and death of the cell. When in place in the chain, it helps produce energy, when sent outside the chain and into the cell, it causes death. If the cell is no longer functioning properly or to protect the greater good of the organism, the mitochondria initiates apoptosis. Many channels must be activated for a cell to commit apoptosis but once they have been activated, its game over for the cell. Once the cell commits apoptosis the organelles and other bits are recycled and there is not a trace from the death that has occurred, neat and tidy like a professional mob hit. A cell that does not die when it is supposed to can cause a ghost of evolution's past to form; cancer. This ghost turns a cell away from the benefit of the organism and changes course to only suit the short term proliferation and growth of the newly selfish cell.
(Picture) The two major pathways of apoptosis. The intrinsic or mitochondrial pathway of apoptosis (left side) involves mitochondrial dysfunction, release of cytochrome c (cyt c) and the subsequent activation of caspase-9 (casp-9) at the apoptosome. The extrinsic or death receptor pathway (right side) is initiated by binding of death ligands to the death receptor and subsequent recruitment of the adapter protein FADD and caspase-8 (casp-8) into the death-inducing signaling complex (DISC).
— There are several reasons that a cell may commit apoptosis:1) Developmental, such as the pruning of webbing from hands to form fingers in the womb. Nearly 80% of neurons are pruned away before birth by the same method to “wire” the brain. 2) Environmental stressors such as toxins and intense sunlight exposure. 3) Viral infections, which in this case, the extrinsic pathway is used more than the mitochondrial pathway. Immune cells come along and see that a cell is “marked” with proteins on the outside of the cell and activate its death. Often the mitochondria are highjacked in certain viral infections by altering some of their pathways to help the virus stay alive longer such as with Hepatitis C. 4) Inefficient energy production.
Our bodies work in a Stalinist like regime and when a cell begins to stride out of favor they usually get the sward, but not always. These rebels can become cancerous and begin to act as a single celled organism from a time before multicellular organisms walked and only thought of themselves, reproducing and taking resources at an astounding rate. The cell becomes a rebel and does not kill itself for the greater good of the organism but rather puts the entire organism in jeopardy so that it may live another day.
Necrosis is the opposite of programed cell death (apoptosis). Instead of an intricate ballet of exchanging reactions, in necrosis the cell ruptures in a more dire and dramatic fashion. In necrosis there is blood on the pavement left in an ally-way with a chalk outline and police wondering what happened. Inflammation is often left in place of the murdered cell. The mitochondria are also involved in this crime scene.
(50 to 70 billion cells commit apoptosis every day in a human body.)
The electron transport chain: The game of hot potato and pumping protons into the gradient
The electron transport chain is located inside the mitochondria on the inner membrane (see pictures below).
Inside the mitochondria on the inner membrane sits the Electron Transport Chain (ETC). There are often thousands of these chains inside every mitochondria and often hundreds to thousands of mitochondria inside each cell. The small proteins labeled “I, II, III, IV” are the complexes that pass electrons from one to the other like a game of hot potato. These electrons come from broken down food stuffs. As these electrons are passed down the chain, protons are pumped out into the inter-membrane space creating a gradient. The game starts at the TCA cycle (Citric Acid Cycle) and moves into Complex I then all the way down to IV where water is a byproduct. These complexes are constantly in flux of being reduced (gaining an electron) and oxidized (losing an electron). This process needs oxygen in order to function which is why it is called aerobic respiration as opposed to anaerobic respiration (respiration without oxygen). What is amazing about this entire process, besides the fact of it happening at all, is the fact that it uses the same methods of positive/negative charges and electron flow like a man made battery would. It has much in common with the energizer bunny.
As electrons pass through these Complexes, protons are pumped out into the space between the inner membrane and the outer membrane, called the inter-membrane space. As the protons are being pumped out, a gradient is formed which pushes the protons in a certain direction, towards ATP Synthase: the worlds smallest rotary motor engine (see the link below to see this tiny motor in action). Once the protons reach ATP Synthase they are driven downwards to turn the “motor” which converts ADP (adenosine diphosphate) to ATP (adenosine triphosphate) by adding a phosphate to ADP. This process is called phosphorylation. This whole act of oxidation and phosphorylation is called Oxidative Phosphorylation (OXPHOS). ATP is then carried to where it is needed in the cell and converted back to ADP to be recycled. The conversion of ATP back to ADP creates mechanical energy for the cell to use to carry out its moment to moment processes. The ratio of ADP to ATP is of the upmost importance in the cell. Around 90% of the energy used in the body comes from the mitochondria and the average person makes about 60 kilos of ATP a day.
One commonality of all life on Earth is the pumping of protons along a gradient to generate energy.
Mine is Bigger Than Yours
The process of Oxidative Phosphorylation yields much more ATP than anaerobic respiration (the formation of ATP without oxygen outside the mitochondria by means of fermentation called glycolysis). Per molecule of glucose the total amount of ATP per rout is: 2 ATP outside the mitochondria (glycolysis) vs. 36 ATP inside the mitochondria (oxidative phosphorylation/aerobic respiration). Beta oxidation produces 129 ATP molecules (whoa!), which is when fatty acid molecules are broken down inside the mitochondria.
Below is an animation of the “motor” ATP Synthase
But Wait, There’s More…
Another source of energy besides glucose that is available for our bodies and brains to use are ketones. Can you guess where ketones are made? You guessed it: in the mitochondria. Ketone bodies are made by our mitochondria in our livers. One study found that a ketogenic diet slowed down mitochondrial myopathy (muscle disease) in mice in part by increasing the number of new mitochondria (mitochondrial biogenesis)(1). More on this to come.
When we break down fats for energy, small molecules called ketone bodies are produced that are used for the production of ATP instead of glucose. This results in improved mitochondrial function, higher levels of ATP from the electron transport chain, and overall cellular health (2). Evidence suggests that the heart may prefer ketone bodies over glucose (3).
Mitochondria are also the initial production site for steroid hormones including cortisol, estrogen, progesterone, and testosterone in which cholesterol is a key ingredient. More on these topics in the articles to come.
There’s a Problem…?
This may sound amazing and grand, which it is, but there’s a catch. Oxidative Phosphorylation (OXPHOS) is happening right next to the DNA of the mitochondria (mtDNA). Unlike the DNA in the nucleus of the cell (nDNA); cozy, warm, and protected, the mtDNA is exposed and open to attack because of its bacterial heritage. As the electrons are shuttled down the Electron Transport Chain (ETC) in a game of hot potato, some are fumbled about. These free electrons are called free radicals and can react with oxygen to form Reactive Oxygen Species (ROS) like Superoxide, which is highly reactive. It can damage just about anything it comes in contact with. These Reactive Oxygen Species can wreak havoc on the mtDNA and cause the mitochondrion to become dysfunctional over time. The free radicals produced inside the mitochondria are our bodies largest source of endogenous free radicals. Our cells have their own antioxidant pathways but sometimes a burst of free radicals is just too much for the mitochondrion, causing it to become dysfunctional. With impaired mitochondria, energy production declines and with it the health of the organism due to the unavailability of ATP to carry out its essential processes. With not enough ATP being produced, the cell commits apoptosis (suicide) and sometimes this happens before its time in certain tissues. This is all fine and dandy in short lived tissues such as the intestinal lining, in which cells turnover almost daily. If they don’t turn over then there can be serious consequences. Cell death in long lived tissues such as the brain or heart can cause serious problems that may not show up for years to come.
With many cells committing apoptosis in long lived tissues, the remaining cells share the workload which puts strain on the existing mitochondria to keep up with the needed metabolic demand and need for ATP. It creates a feedback loop: less cells to do the work of many, fewer mitochondria to generate ATP, more stress on the mitochondria means more free radicals, more free radicals means more mutations, and more mutations means more dysfunctional mitochondria taking over a given tissue…and the tragedy continues.
But alas, there is a solution: the mitochondria can divide and multiply — mitochondrial biogenesis. A signal is sent from the nucleus when to divide and a new equilibrium has now been reached, but of course this can’t go on indefinitely in cells due to their compact size and need for room to carry out other cellular functions. It can get crowded in there. A few cells committing apoptosis in the heart is expected but when a threshold is reached and many of these long lived cells die off, heart contractions can weaken which can lead to cardiovascular diseases. Likewise with brain cells (neurons), when a few die, it’s the cost of doing business, but when the threshold is met, dementia and other neurological diseases can begin to flourish. (4) , (5) Luckily growing new brain cells was once thought to be nonsense, we now know this to be false. Neurogenesis is the growing of new brain cells and happens at any stage of life with the right circumstances and the right “fertilizers”. Mitochondria play as central regulators of this process. (6)
These enemies of the state, or free radicals actually aren’t all bad. It was once thought that all free radicals were bad and they should be cleaned up at all costs with huge amounts of antioxidants. We now know this to be false, very false. As bad as it sounds to have Oxidative Phosphorylation (OXPHOS) happening near the mtDNA, it really isn’t all bad. You may be asking yourself why mother nature would put a nuclear power plant next to a delicate library that has occasional fire balls shot at it — well, many people have asked the same question with many answers but none as elaborate as the genius of the mitochondrion. As electrons pass down the ETC some electrons are fumbled, yes, and they turn to free radicals that can cause damage to the organelle, but these free radicals also act as messengers to the mitochondria. Taking too many supplemental antioxidants can actually hinder this process.
The process is as follows: when there are very few free radicals being produced and supply/demand of ATP is in equilibrium, the mitochondria carries on with its duties and lives happily slaving away for the benefit of Mr. Kite. If the ETC has a sudden leak of free radicals, this sends a message that there is a problem that needs to be addressed. Whether it be making more of the complexes in the ETC or uncoupling the Proton Gradient to make up for the sudden leak in free radicals, you can be sure that it will be addressed in healthy mitochondria. This is where those 13 critical subunits mentioned earlier that are left in the mtDNA come into play. It keeps these genes so close to the action in order to efficiently correct the deficit. The 13 subunits that the genes code for are all proteins that sit on the inner membrane of the mitochondria. A message is sent to the nucleus from the mitochondria via a pathway called the retrograde response (yes, the mitochondria can actually send messages to the nucleus instead of the usual messages being sent from the nucleus to everything else; the nucleus also communicates with the mitochondria in turn) to make the other proteins that make up the rest of the complex/complexes needed in the ETC. The 13 subunits coded by the genes inside the mitochondria that sit on the inner membrane act similar to a foundation or beacon so that when the nucleus sends the other proteins to complete the complex/complexes, they align perfectly around the subunits…unless the genes coding for the subunits have been damaged.
There is a dark side to free radicals but it isn’t as dark as once imagined. The entire system of free radical leakage works like a special thermostat. When the air in the room (free radicals) goes above or below a set temperature, the air is kicked on or off (building complexes/uncoupling the proton gradient) to remain at a certain temperature (energetic demand).
The Economics of Mitochondria and the Greatest Fumble in Sports History
Excessive caloric intake of a sedentary person introduces an abundance of fuel to the body, this fuel is turned to a slew electrons which can block up the ETC if the demand for ATP is low. A blockage in the ETC means excessive free radical leakage. If the free radical burst is too much or the excessive eating does not stop, the mitochondria can not efficiently correct the problem. A blockage in the ETC means excessive free radicals damaging the mtDNA or oxidizing the membranes, which may be why obesity is linked to so many degenerative diseases and linked to 13 types of cancer. Think of it like trying to juggle many balls at the same time; you are way more likely to drop one the more you add. On the other hand, If the supply for ATP is being matched by its demand, the electrons run smoothly down the ETC with little leakage. This could be why caloric restriction extends lifespan in mammals even though little is known about the mechanism of how it exactly achieves lifespan extension. One theory is that of the mitochondria and the above mentioned supply/demand of ATP and electron flow. Caloric restriction differs from famine in that a famine induces nutrient deficiencies, caloric restriction is often practiced by eating nutrient dense foods but lowering overall calories by about 20% or more than one would usually eat. On the mitochondrial side of things, this would mean a smoother running ETC with fewer free radical leaks and less mtDNA damage over time. Less balls to juggle, less chances of them dropping. The only issue with caloric restriction is that over time it becomes an issue: no one likes feeling hungry for years on end. Adherence seems to be better suited for humans in short bursts or in practicing intermittent fasting.
Eskimos and Africans
The Proton Gradient isn’t just used to generate ATP by sending the protons down to ATP Synthase. The energy built up in the gradient can also be dissipated as heat- ever wonder where your body heat comes from? The dissipation of energy built up in the proton gradient can also cause the ETC to run smoother if it becomes “clogged” with electrons. When the ETC becomes jammed up with many electrons and there is an ample supply of protons in the gradient, ATP Synthase grinds to a halt and Uncoupling Proteins “uncouple” the proton gradient which then gets released as heat. It can be thought of as a reservoir that fills up and needs to be released if it becomes too full, like a dam. You can imagine that people who have lived in cold climates for generations have an advantage at keeping warmer than someone from a hot climate. In a cold climate these individuals use the uncoupling of the proton gradient to produce more body heat. As mentioned, because these protons are being released, they are no longer being sent down to ATP synthase to drive the motor to make ATP. This would mean you would need to eat more food or more calorically rich food, such as blubber or fatty fish to maintain the bodies energy requirements. These foods happen to be a main staple of Eskimos and other extreme cold climate communities around the world to keep the body’s metabolic requirements in equilibrium.
In Africa, the advantage would be to produce less heat due to the hot climate. With less uncoupling proteins available the gradient isn’t released as much as, say, an Eskimo. Instead the protons are pumped to ATP synthase to drive the motor to form more ATP. Due to the “African” not “Uncoupling the Gradient”, this can cause issues if the stores of ATP are not being used up. Like our example of a sedentary person eating a large meal and the demand of ATP is low, the proton gradient would normally mitigate some of the free radicals being produced by the backed up ETC by still allowing electron flow but dissipating the protons in the gradient pumped from the complexes in the chain. With fewer Uncoupling Proteins, the gradient (reservoir) fills up with protons and the ETC has an excess of electrons trying to flow down the chain but demand for ATP is low. Both the gradient and the ETC are full, bursts of free radicals begin to spark and mtDNA damage is bound to happen. This could be why incidences for type 2 diabetes is higher in African Americans than any other race besides Native Americans/Native Alaskans. As for the Native Alaskan/Native American, these numbers in Type 2 diabetes could be associated with a move away from their traditional high fat diet and more towards a standard high carbohydrate “American” diet and a sedentary lifestyle. More on this later.
The Problem Continues: Blind Garbage Men
As the SOS Mitochondrial Theory would suggest, when the mitochondrial membrane becomes more permeable due to the oxidation from free radicals produced by OXPHOS (oxidative phosphorylation), a Blind Garbage Man swoops in and carries it away: the Lysosome. This process is called mitophagy. These organelles are the garbage men of the cell, they are responsible for taking out the trash and incinerating it or recycling it. This is why older people have relatively healthy mitochondria when it was once thought as we age the free radicals mutate our mitochondria and cause dysfunction in the organism over a lifetime. This still happens but on a much smaller scale than previously thought due to mitophagy (about 1% of cells contain nothing but mutated mitochondria). In a normal healthy cell the mitochondria go through rounds of fission and fusion where they repair genes and the damaged mitochondria get taken away by the lysosome. What ends up happening in some tissues of the body is that the mitochondria with healthy genes (none mutated and a smooth running ETC) get marked for the lysosome because of their membranes have become more porous due to the free radicals produced during OXPHOS, a cost of doing business. This happens over time (the average life of a single mitochondria is about two weeks). These otherwise healthy mitochondria get scrapped and taken to the garbage heap while some mutated mitochondria escape the blind vigilante due to their membranes appearing healthy. But as mom always says,… “what’s on the inside matters”. Some of these seemingly healthy mitochondria are in fact devils in disguise. The genes for OXPHOS have been knocked out entirely from bursts of free radicals hitting just the right (or wrong, depending on how you look at it) genes. The reason its membrane looks and appears healthy is because with OXPHOS turned off, it isn’t producing any more free radicals from the ETC to oxidize its membrane. This would mark it for Mr. Magoo to come and bag it. So, it escapes untouched while the rest of the mitochondrial lot is left with the labor of generating ATP due to the mutant mitochondria having OXPHOS knocked out. The labor is now to be spread across smaller numbers. These mutant mitochondria live off the labors of healthy mitochondria. Some speculate that this may be a darwinian survival advantage for the mutant organelles to escape death.
Now for the kicker — Even though these mutant mitochondria are not producing free radicals from OXPHOS, they are producing free radicals from an over active TCA cycle, which feeds the Electron Transport Chain its electrons. With no where to put the electrons and the need to get rid of them to save itself the potential damage from them, it shuttles them outside the mitochondrion. With these free radicals now outside the mitochondria and into the cell they react with whatever they come in contact with, sometimes harmlessly forming water and sometimes forming harmful Reactive Oxygen Species (ROS).
Not a big deal, it’s only the 1% of cells that contain mutated mitochondria. Well, it’s not a big deal as long as these Reactive Oxygen Species such as superoxide don’t come in contact with something that shuttles around the body going to and fro, to and fro... Enter LDL Cholesterol. This is what is sent from the liver to the rest of the body where it’s needed for general maintenance and hormone synthesis. LDL cholesterol is a lipoprotein that gets shuttled around the body delivering cholesterol to where its needed. With oxidized cholesterol being delivered instead of a healthy payload you could imagine the havoc this would have on the body from just a few cells containing mutant mitochondria. Let’s paint a picture: if the damaged cholesterol is sent to a site of inflammation for cellular repair, it would just make the problem worse. If it is sent to make steroidal hormones such as testosterone or estrogen, the cell would not be able to synthesize them lending the work to the rest of the surrounding cells to make up for the loss to keep the body in homeostasis. This again, puts a higher work load on available mitochondria causing more mutations. We have another feedback loop: with too few mitochondria efficiently working, the nucleus sends a signal for the mitochondria to divide. This can further compound the problem if the mutant mitochondria divide time and time again because they have evaded the lysosome (blind garbage man), and the healthy non mutant mitochondria do not divide due to their selection for death by the lysosome because of their porous membranes. In otherwise healthy tissues the division of mitochondria would be preferred due to the body needing to regulate ATP production to keep up with demand and metabolic requirements.
(Picture) The above picture is an illustration of mitochondria dividing and going through mitophagy. According to SOS, the mitochondria with mutated genes that have a knocked out OXPHOS divide and escape the lysosome, eventually taking over a given cell and causing problems. Otherwise healthy mitochondria go through mitophagy and are culled from the population due to the free radicals oxidizing their membranes from an active OXPHOS, a completely normal process that keeps the cell healthy and vibrant. This theory was proposed by Aubrey de Grey.
With many mitochondria per cell, the labor of making ATP is spread out evenly between them as we talked about above. Think of it like a labor force trying to complete its tasks. You can either have a large labor force with the work spread out between them and occasionally they get bored and damage the walls or a small labor force with no free time and always working at max capacity, no vacations. Who would burn themselves out and cause more damage in the long run? Which is it?
So, the short of the long of it is: As we age cells rely more and more on the remaining mitochondria. With defective mitochondria, the cell creates a new equilibrium and divides its labor force out. The act of dividing can be a great thing for maximizing ATP output or it can be a negative thing such as a cell with mutant mitochondria that have a selective advantage for surviving another day. Luckily these cells will be short lived due to not enough ATP being produced which would cause apoptosis or necrosis. By the time this has happened, the damage has been done throughout the body by means of spreading defective payloads and apoptosis/necrosis of long lived tissues, causing a higher demand on the remaining cells to keep up with the metabolic requirements.
On top of these feedback loops there is another that is just now beginning to be understood. As mentioned earlier, the mitochondria can communicate with the nucleus and the nucleus can communicate back to the mitochondria. As we age, a Hypothesis by David Sinclair is that this communication gets degraded over time. You can think of the mitochondria and the nucleus of the cell being a married couple due to the mitochondria being a once free living organism. The mitochondria moves in with the cell, the nucleus and mitochondria are happy, newly married. They have the usual honey moon and celebrate anniversaries of marriage but after some time they grow apart and the communication between the two becomes rocky. We are now at the stage of most couples that have been married for some time. How does this issue become resolved? Better communication. One of the molecules that helps in this situation, sort of like a marriage counselor, is NAD+. NAD+ is used in the Citric Acid Cycle to carry electrons into the ETC. NAD+ gains electrons making it reduced (NADH), then passes the electrons into the chain turning NADH back into its oxidized form of NAD+. It also has more functions outside the mitochondria. More on this molecule in articles to come.
Another product of mitochondrial dysfunction is cellular senescence. When a cell becomes senescent it stops dividing prematurely and sits there taking up valuable real-estate. It basically becomes a zombie. Due to the cell becoming senescent, mitophagy is impaired, making Oxidative Phosphorylation efficiency decrease and Reactive Oxygen Species production increase causing further dysfunction. Cellular senescence is believed to be one of the driving factors of aging.
What the Problem looks like
There are many, many mitochondrial diseases which are genetic. A brief look around google by searching “mitochondrial diseases” will put a sour taste in your mouth. These diseases result from mutations in the mtDNA from birth or from early life and can be catastrophic. They can often result in death. There are other, less obvious diseases in which the mitochondrion is the central or indirect player: Chronic Fatigue Syndrome, Neurodegeneration, Type 2 Diabetes, Alzheimer’s, Multiple Sclerosis, Fibromyalgia, Depression, Cancer, Cardiovascular Diseases…and the list goes on and on and on. Studies are currently underway to look at the role of mitochondria in Type 2 Diabetes which is a less obvious place to look when compared to a disease like Chronic Fatigue Syndrome. For example, Type 2 Diabetes is a result from the ETC becoming backed up and fumbling more electrons which leads to mutations over time often caused by over consumption and not depleting ATP stores (exercise). A hallmark of Type 2 Diabetes is insulin resistance. People who have Type 2 Diabetes often have a vicious feedback loop in play starting from years before the disease sets in: mitochondrial damage, lipid accumulation in cells causing more mitochondrial damage, then insulin resistance leading to a higher metabolic rate to make more insulin which strains the tissue further leading to more damaged mitochondria and the die off of beta cells in the pancreas finally resulting in high blood sugar and an attempt at more insulin being pumped from an already stressed pancreas keeping the cycle going. Type 2 Diabetes is more common in African Americans and Native Americans. This could be due to the fact that evolutionarily they don’t have as many Uncoupling Proteins (proteins that “uncouple” the proton gradient to be “released as heat”) because they didn’t need as much body heat in Africa due to the extreme climate. With less uncoupling of the ETC, the chain can become backed up with electrons more easily if the supply of ATP is above the demand causing mutations and dysfunction due to free radical bursts. The body is full of these vicious feedback loops with the origin being that of the mitochondria. Native Americans could have a similar issue but not resulting from uncoupling proteins, but from radically changing their diet to adopting a high carbohydrate “American” diet rather than the traditional diet once eaten in their culture and a sedentary lifestyle.
Social Networking & Blind Surveillance
Mitochondria can fuse together into vast networks in the cell. The exact function of why these creatures do this is currently unknown. There are a few hypotheses surrounding the subject. As mitochondria fuse together, they share information with one another, such as their DNA. They could also be sharing information on another level, such as with metabolites in the Citric Acid Cycle, ATP and ADP, and membrane permeability. Why would they do this? These metabolites and their concentrations could tell a lot about the health of their neighbor and thus the status and health of the cell. As they fuse, large tubular networks of mitochondria can be formed. Dysfunctional mitochondria can trade out genes with neighbors and have social hour. This gives rise to another means of quality control besides mitophagy. The blind garbage men, or lysosomes, can pick off left out mitochondria that did not join with the network, dysfunctional or not. Sometimes these cellular incinerators are full of garbage already, which we talk about in Part II.
What makes the mitochondria fuse together in the vast networks? Is this some sort of magic? It appears that when there is a surplus of ATP around the cell, the mitochondria can read this. It tells them “hey, there are some really great preforming guys in here… we should hang out!” Then they fuse and the mitochondria who may be struggling get to trade genes and thus preform better when they go through fission (divide out). So, what happens when there is rarely an energy (ATP) surplus around and these guys don’t get to have cocktails together? A heavy reliance upon the blind garbage men are required and if there are issues involving lysosomal degradation then things get messy, such as the SOS theory mentioned above would suggest.
Then there is Blind Surveillance which is selective towards mitochondria that fuse. Functional mitochondria are more likely to fuse, but not always. This leaves dysfunctional mitochondria fragmented from the network and more likely to be picked off by lysosomes during mitophagy. Those that don’t join, die. In each of these variations, selective fusion or non selective fusion, both add another layer of quality control in the cell. Arguably, these forms are more prudent than mitophagy. The act of fusing into larger mitochondrial networks could induce a stronger retrograde signal (communication to the nucleus). Stronger signals means better communication, better communication means a healthier cell.
So what do we do?
All of this seems inevitable and some of it is, but a lot of it can be mitigated through practicing a lifestyle. In the next few articles we will be discussing these approaches: diet, supplementation, HIIT, light therapy, hot and cold exposure, inflammation and toxins.
Speculations and Further Questions
The free radical theory of aging is dead but like a phoenix from its ashes has arisen a new theory of aging with many components but at its center of course, is the mitochondria. Mitochondria: making complex life possible, producing over 90% of your bodies energy, making the warm blooded revolution occur as well as having a hand in why there are two sexes, and causing cellular suicide when appropriate. These little guys deserve the recent spurge in popularity and research. As discussed, the mitochondria are ground zero for many emerging diseases in the body. We are still learning a great deal about free radicals as messengers in the mitochondria and about their role in diseases but have much to learn. This does not take away from the importance of trying to upgrade these little creatures. Who couldn’t use some extra battery life?
Quorum Sensing and More Speculations
Bacteria in the world and in our guts can actually communicate from strain to strain and species to species. They check to see if a given environment is safe or viable and also to see who their neighbors are. This is called Quorum Sensing. (7) It is well known that the bacteria in our guts also modulate our nervous system and behavior via the Vagus Nerve and other means. The vagus nerve is a nerve that travels from the gut to the brain. It can be thought of an information superhighway. Bacteria in our guts make byproducts such as serotonin, enzymes, and short chain fatty acids that our brains and body use and could not live without efficiently. Is it possible then for mitochondria, a once bacterium, to communicate with other bacteria in our bodies? This is entirely speculation of course, but what if by an undiscovered mechanism mitochondria are in fact communicating with other bacteria in our guts and bodies; sending chemical messages to like creatures throughout the Petri dish that is our body. We are becoming less and less human as science progresses and becoming more of a composite; a juxtaposition of living organisms cooperating and sometimes fighting with one another on what we would consider our own land. It is now a nation divided. What does it mean to be human? What will science discover tomorrow that we don’t know today?
Tune in next time for Part II in this series of improvement. For now, be well and mind your mighty mitochondria.
Resources and further reading:
Power, Sex, Suicide by Nick Lane
The Vital Question by Nick Lane
Mitochondria and the Future of Medicine by Lee Know
The Mitochondrial Free Radical Theory of Aging by Aubrey de Grey
Navigating Metabolism by Navdeep S. Chandel
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