What Allows Us To Endure?

In the grand scheme of life, it all boils down to one fundamental truth: we need energy. It's the essence that keeps us alive. Meet adenosine triphosphate, or simply ATP – a name you've likely encountered before. But why is ATP the lifeline, and why does our existence hinge on it?
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Picture ATP as the electric power to a light bulb; without it, the bulb remains in the dark. Similarly, our body's cells rely on ATP as the catalyst for numerous vital biochemical processes. These processes, akin to the electric light's need for power to shine, come to a standstill without ATP. The outcome of prolonged ATP deficiency? The lights go out, metaphorically and literally – a gateway to the realm of death.

What ATP actually is

ATP is really cool, not just because it's a key player in keeping us all alive, but because it operates much like a spring. Think about when you compress a spring, loading it with potential energy. This energy is then released as the spring expands back to its decompressed state. Similarly, ATP, as a molecule, stores potential energy in its chemical bonds.

This stored energy becomes available during a specific biochemical process – hydrolysis. In this process, ATP is broken down by the addition of water, breaking the high-energy chemical bonds and releasing energy. As we've previously discussed, this chemical energy becomes a valuable resource for cells in various biological processes.

Now, tying it back to endurance and what allows us to endure, it's ATP that muscle cells and fibers use for contraction. Whether it's running, swimming, or lifting weights, adenosine triphosphate is the driving force behind it all.
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Where Humans obtain ATP

Humans, like other animals, have evolved the ability to generate ATP from biological compounds found in the food we consume, such as carbohydrates, lipids, and proteins. The significance of this process becomes evident when we consider that each time an ATP molecule releases its stored energy, it undergoes hydrolysis, breaking down into ADP and inorganic phosphate, losing a phosphate group. Fortunately, it’s theoretically possible to reverse this process and restore the energy by adding back the separated phosphate group, so this is not the end of the line for the consumed ATP.

Our body has an ingenious recycling system in place. The reduced molecule ADP is reclaimed and converted back into the higher-energy molecule through a process known as phosphorylation. This involves adding a phosphate group, effectively restoring the lost energy. But it's crucial to recognize that this recycling process demands energy itself.

By revisiting the macronutrients present in the food we consume—carbohydrates, lipids, and proteins - we now understand why these nutrients play a vital role: Supplying the energy required for synthesizing ATP from ADP and inorganic phosphate.
Our body's ability to digest external sources, such as fruits, grains, or legumes, and break down their high-energy macronutrients is therefore the cornerstone of our energy production system. This system's ultimate objective is to replenish our universal energy currency, ATP.
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Why Not Use External Sources as Immediate Energy Supply?

Let's delve into why ATP is even more remarkable. When harnessing the energy stored in carbohydrates, our body takes a fascinating route. First, it must undergo the process of digestion, breaking down the complex chains of saccharide molecules that make up carbohydrates—derived from the Ancient Greek word σάκχαρον (sákkharon), meaning 'sugar.' This process results in simple sugars like glucose, fructose, or galactose—terms you've likely encountered before.

What makes this journey intriguing is that a single glucose molecule stores far more energy than an individual molecule of adenosine triphosphate (ATP). This surplus of energy, however, poses inefficiencies when it comes to the rapid and controlled release required by various biological processes in the human body. Glucose, if used directly, would unleash an overwhelming amount of energy, uncontrollable for our cells. Hence, it needs to undergo multiple chemical breakdowns before it becomes a form our cells can effectively work with.

Moreover, ATP boasts the advantage of easy transport within the cell to different locations where energy is needed. The controlled breakdown of glucose into ATP enables cells to distribute and utilize energy precisely where it's required. Picture ATP as the compact battery you typically purchase for devices like TV remotes or small flashlights. It stores enough energy to power whatever it's used for, all while being easy to handle and transport. In contrast, glucose would be akin to attempting to use a massive car battery to supply electrons for your modest egg timer.
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How Do We Generate ATP?

Let's now explore the various ATP-synthesizing systems within our human biology, distinguished by a crucial factor: oxygen.

In the presence of oxygen, our cells efficiently synthesize ATP through a process known as aerobic respiration (from the Greek ἀήρ = air and βίος = life). Aerobic respiration theoretically yields up to 38 ATP molecules from one glucose molecule. However, practical considerations, including potential inefficiencies in the process, bring the likely range to around 29-32 ATP molecules. Despite these variations, it remains an impressive ratio and the preferred method for most human cells to meet their energy demands throughout the day. This emphasizes the critical role of oxygen in our energy production system – our largest and most efficient.

Humans also possess the ability to generate energy without oxygen, a process we'll explore later in this article.
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Let’s talk about the essential steps of Aerobic Respiration:
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  1. Glycolysis

  2. The Link Reaction

  3. Citric Acid Cycle/Krebs cycle

  4. Electron Transport Chain

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For a better and easier understanding of each step of the aerobic respiration, let’s begin with a metaphorical example:
Imagine a cell as a small power plant that needs to generate electricity (ATP) for various activities. Glucose is like a fuel source that the power plant wants to use to produce electricity efficiently.

In the first step, glycolysis is like the process of breaking down large logs of wood (glucose) into smaller pieces (pyruvate). These smaller logs are easier to handle and transport.

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Glycolysis

Much like many terms in biochemistry, glycolysis reveals its meaning through its Greek roots: "glykys," meaning "sweet," and "lysis," which translates to "to split." Utilizing various enzymes, our cells initiate the breakdown or splitting of a single glucose molecule right in the cytoplasm. This process results in the formation of two pyruvate molecules, crucial for the ongoing synthesis of ATP. However, glycolysis is not just about that; it also yields 4 ATP, 2 NADH, and 2 H+. On the flip side, glycolysis consumes resources, leading to the following equation:
Glucose + 2 NAD+ + 2 Pi + 2 ADP 2 pyruvate + 2 ATP + 2(NADH + H+)

Until this point, none of the intermediate steps in glycolysis required oxygen. Now, it's up to the cell to decide the fate of pyruvate, a decision heavily influenced by the redox state. The redox state essentially indicates whether there is a sufficient or insufficient supply of oxygen.

In the presence of adequate oxygen, pyruvate continues its journey along the aerobic energy pathway. If oxygen is limited, this reduced molecule takes the anaerobic route for ATP synthesis, requiring a series of different biochemical steps, which we will get to later in this article.

Let’s come back to our metaphor: The power plant wants to extract the maximum energy from the smaller logs. So, it converts each small log (pyruvate) into a more concentrated and energy-rich fuel, like converting chopped wood into wood pellets. This conversion is done through oxidative decarboxylation.

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Oxidative Decarboxylation

Before proceeding to the next step, pyruvate must be transported into a mitochondrion, a task facilitated by a carrier protein. Once inside the mitochondrion, the process of oxidative decarboxylation, often referred to as "The Link Reaction," begins. This catalytic process involves the removal of one carbon dioxide (decarboxylation) from pyruvate, with its electrons transferred to NAD+, resulting in the formation of NADH + H+. The detached carbon fragment then combines with coenzyme A (CoA) to produce acetyl-CoA. The equation representing this process is as follows:

Pyruvate + Coenzyme A + NAD+ acetyl-CoA + NADH+H+ + CO2

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Now, the power plant has these energy-rich wood pellets (acetyl-CoA). It puts them into a furnace, which is the citric acid cycle. The furnace burns the wood pellets, releasing a lot of heat and capturing that energy in the form of high-energy electrons (NADH and FADH₂).

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The Citric Acid Cycle

Also known as the "Krebs cycle" this series of chemical reactions serves to release stored energy through the oxidation of acetyl-CoA. All of these reactions unfold within the mitochondrial matrix. At each step of this cycle, the energy stored in the original glucose molecule is systematically released. The mitochondrion's objective is to harness this energy by utilizing it in a cascade of reactions, culminating in the generation of high-energy molecules like NADH and FADH₂. The chemical equation is as follows:
Acetyl-CoA + 3 NAD+ + FAD + GDP + Pi + 2 H20 CoA-SH + 3 NADH + FADH2 + 3 H+ + GTP + 2 CO2

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The power plant takes these high-energy electrons and sends them through a series of turbines, which is the electron transport chain. As the electrons flow through the turbines, they generate electricity. This energy is then used to charge up a battery (ADP ATP).

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Electron Transport Chain

The electron transport chain comprises multiple protein complexes situated in the inner mitochondrial membrane, namely Complex I, II, III, and IV. NADH and FADH2 play a crucial role by donating their electrons to Complex I and II. Each complex in the chain facilitates the transfer of electrons to the next, allowing Complex I, III, and IV to pump protons from the mitochondrial matrix through the inner mitochondrial membrane into the intermembrane space. This process establishes a proton gradient, serving as potential energy.

Another essential player in this complex system is ATP synthase (Complex V). ATP synthase consists of two primary components: the rotor, embedded in the inner mitochondrial membrane, and the catalytic knob, protruding into the mitochondrial matrix. Protons pumped into the intermembrane space also generate an electrochemical gradient due to the positive charge of protons.

When this gradient reaches a certain level, protons flow back into the mitochondrial matrix through ATP synthase. This movement of protons through Complex V exerts force on the rotor component, causing its rotation. As the rotor turns, conformational changes occur in the catalytic knob of ATP synthase, ultimately leading to the synthesis of ATP.

Interestingly, after ATP production is complete, oxygen plays a crucial role for the first and only time in completing aerobic respiration. To sustain the continuous generation of ATP through the electron transport chain, the initially accepted electrons from NADH and FADH2 must be handed over to an electron acceptor. Otherwise, they would back up within the chain, causing a buildup and disrupting the flow. Oxygen takes on the role of accepting electrons and combines with protons to form water (H₂O).

The simplified equation to illustrate the overall process looks like this:

NADH + H+ + FADH2 + 1/2 O2 + ADP + Pi NAD+ + FAD + H20 + ATP

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These were the 4 steps of aerobic respiration using glucose as its initial energy source. However, our cells aren't limited to using just glucose for aerobic ATP synthesis; they can also tap into the energy potential of fatty acids and amino acids.

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Beta-Oxidation

This metabolic pathway comes into play when fatty acids serve as the primary energy source for ATP generation. In general, fatty acid oxidation yields a higher amount of ATP compared to the oxidation of glucose due to their higher energy density. This pathway leads to the formation of acetyl-CoA, an essential molecule we've already encountered as an intermediate in the breakdown of glucose for ATP synthesis. Acetyl-CoA is subsequently processed in the citric acid cycle and the electron transport chain. Notably, the formation of acetyl-CoA marks a significant difference from anaerobic metabolism, where acetyl-CoA does not play a role. Here are the steps of making of adenosine triphosphate from fatty acids:
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  1. Activation: First, our cells need to activate the fatty acids in the cytoplasm by acyl-CoA synthetase. This enzyme catalyzes the reaction between the fatty acid and coenzyme A (CoA) to form a fatty acyl-CoA molecule. This activation of fatty acids is a crucial step that primes them for entry into the mitochondrial matrix.

  2. Transportation: The activated fatty acyl-CoA is then transported into the mitochondria, where beta-oxidation takes place. This transport process involves a carnitine shuttle system.

  3. Beta-Oxidation: Once inside the mitochondria, acyl-Coa undergoes a cyclical process that involves a series of enzymatic reactions leading to the removal of two-carbon units in the form of acetyl-CoA.

  4. Entering the Citric Acid Cycle: The generated acetyl-CoA enters the citric acid cycle, and through subsequent reactions, it contributes to the production of NADH and FADH₂. These carriers then feed electrons into the electron transport chain for ATP synthesis.

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Utilizing of amino acids

While amino acids are not the primary or preferred source of energy under normal conditions, their utilization is a dynamic and important aspect of cellular metabolism, especially in situations where other energy sources are limited or during specific metabolic demands.

The following shows the successive steps of this metabolic energy path:

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  1. Transamination and Deamination: To start the utilizing of amino acids, they have to undergo transamination and deamination, leaving only the carbon skeleton of the amino acid. This process produces ammonia(NH3).

  2. Conversion to Intermediates of Glycolysis or Citric Acid Cycle: The carbon skeleton is often converted into intermediates that can enter glycolysis or the citric acid cycle like acetyl-CoA, NADH or FADH2. The specific fate of the carbon skeleton depends on the amino acid's structure and the metabolic needs of the cell.

  3. Ammonia Detoxification: The ammonia produced during the deamination of amino acids is toxic and needs to be detoxified. This happens to be in the liver, where ammonia is converted into urea, a less toxic compound, which is then excreted in the urine.

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With that, we've covered our body's capacity for aerobic respiration, the process of energy generation in the presence of oxygen. Now, let's delve into what unfolds when oxygen becomes scarce. As the cell recognizes insufficient molecular oxygen to sustain the typical electron transport chain process where oxygen plays a pivotal role.

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Anaerobic Respiration:

A lack of oxygen can arise from various factors, with a common one for physically active individuals being the heightened energy demand from muscle cells during activities like running.

In this scenario, our body activates more mitochondria in our cells, supplying these powerhouses with nutrients and oxygen. As we engage in running, our energy demand and oxygen consumption both increase. As mentioned earlier, aerobic ATP synthesis is our body’s preferred method for generating energy. However, during intense exertion, the oxygen consumption of cells surpasses the supply through our respiratory and cardiovascular systems.

This results in the disruption of the electron transport chain, where oxygen fails to act as the final electron acceptor. Consequently, pyruvate, which would normally proceed into the mitochondrion under sufficient oxygen supply, converts into lactate through lactic acid fermentation, utilizing NADH and regenerating NAD+. This enables the cell to continue energy production through glycolysis, requiring NAD+ for operation and yielding a total of 2 net ATP.

It's obvious that this form of ATP synthesis is inefficient and not a sustainable long-term solution. Cells prefer aerobic respiration for optimal ATP production. When oxygen becomes available again, cells shift back to aerobic metabolism, using the more efficient electron transport chain to regenerate NAD and resume energy production.

A crucial reason for cells favoring aerobic pathways is that anaerobic respiration inevitably produces lactic acid. Due to its acidity, the compound impacts cellular pH, causing disruptions in biochemical processes. Excess lactic acid is cleared into the bloodstream, transported to recycling stations like the liver. When the body struggles to keep up with increasing lactic acid levels, fatigue sets in. Muscle cells can't sustain high-demand efforts due to insufficient ATP. To comprehend the effects of lactic acid, it's essential to note that an acidic pH inside the cell downregulates glycolysis, resulting in progressively less ATP production, even during anaerobic respiration.

So, what is anaerobic respiration actually good for?

One major advantage, in comparison to the lengthier process of further breaking down glucose or fatty acids through the Link Reaction or the Citric Acid Cycle, is its speed – significantly faster. However, this speed comes with a trade-off as there are fewer processes involved in providing ATP. This, in turn, explains the inefficiency, as much of the stored energy in glucose cannot be fully utilized.

Anaerobic respiration becomes crucial in situations where mitochondrial respiration would take too much time. This is evident, for instance, at the beginning of a run or when the energy demand suddenly exceeds the rate at which ATP is supplied by the aerobic mechanism. In such cases, an alternative ATP-synthesizing pathway, such as anaerobic respiration, has to be activated.
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Here are the summarized steps of anaerobic respiration:

  1. Glycolysis: takes place in the cytoplasm and involves the breakdown of one molecule of glucose into two molecules of pyruvate through several enzymatic reactions. This proves does not require oxygen and is the same in both aerobic and anaerobic conditions.

  2. Conversion of Pyruvate to Lactate: In the absence of oxygen, the pyruvate produced during glycolysis is converted into lactate through an enzyme called lactate dehydrogenase. This reaction involves the oxidizing of NADH to NAD, which is a crucial aspect of anaerobic respiration to sustain glycolysis. During glycolysis, NAD is reduced to NADH. Regenerating NAD allows glycolysis to continue by ensuring the availability of NAD as a coenzyme (Remember the fact that NAD+ levels decrease during oxygen scarcity caused by NADH’s inability to transfer its electrons to the ETC).

  3. Energy Production: While lactic acid fermentation does not produce as much ATP as aerobic respiration, it allows for the continued production of ATP during periods of oxygen deprivation. The ATP produced through glycolysis is the primary source of energy in anaerobic conditions.

  4. Lactic Acid Accumulation: Lactate, what is a byproduct of lactic acid fermentation, accepts the hydrogen ion that comes from the reduced NADH, leading to the formation and accumulation of lactic acid. Increased levels of lactic acid contribute to temporary muscle soreness and fatigue. During regenerative lower efforts of physical activity, lactic acid is eventually transported to the liver, where it can be converted back to pyruvate and used in gluconeogenesis to generate glucose.

You now know about the two main energy productions of our body: aerobic and anaerobic-lactic (meaning ATP is produced under the absence of oxygen and accumulation of lactic acid).

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But there’s another, a third, and simultaneously the final part of our ATP synthesizing capability:
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Phosphocreatine Hydrolysis (anaerobic-alatic)

Anaerobic-alactic essentially means, as you might already guess, the generation of ATP without the production of lactic acid and the necessity for oxygen.
Sounds pretty impressive, right? Like the ultimate pathway for synthesizing ATP, no limitations through acidity or a lack of oxygen. But don't let me fool you; there are limitations, and at the same time, its benefits.

The so-called phosphagen system operates on phosphocreatine. It's a high-energy molecule found in cells, particularly in tissues with high and fluctuating energy demands, such as skeletal muscle. It serves as a rapidly mobilizable reserve of phosphate groups that can be used to regenerate ATP during intense and short bursts of activity like sprinting or lifting weights.

In skeletal muscle cells, for example, phosphocreatine is often stored in higher concentrations than ATP. Creatine kinase, an enzyme present in the cells, facilitates the reversible transfer of a phosphate group between ATP and creatine (forming phosphocreatine). When energy is needed rapidly, the phosphate group from phosphocreatine can be transferred to ADP to regenerate ATP by a process known as hydrolysis.

This way of fulfilling the cellular needs of ATP during activity lasts for less than 20 seconds. Approximately. It varies between athletes, but one thing becomes pretty clear: its time limit.

This energy reserve is not a reliable source when it comes down to longer bouts of physical effort like swimming or working out. But obviously, it's like the Usain Bolt under the body's energy productions, it’s always first. Making it indispensable for our skeletal muscles.

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What allows us to endure?

Now, you grasp the fundamental factor that enables us to thrive in physical activity: our body's internal fuel known as ATP. It's akin to the electricity powering Elon Musk's latest Tesla – without it, movement, let alone life, becomes impossible.
As the final part of this article, let’s take a precise look at when our body uses which ATP generating pathway during a run:

Energy sources during running
Energy sources during running

Image Source Quora

This piece on human energy systems is a segment of a larger series titled "What Allows Us To Endure," inspired by Dr. Andrew Huberman. Keep an eye out for forthcoming articles delving into other essential aspects of our body that contribute to our endurance. Stay tuned for more.