Many people in the US suffer from fatigue or lack of energy. According to the CDC, at least 1 million individuals in the United States have chronic fatigue syndrome and only 20% are actually diagnosed [1]. They even estimated the annual cost surrounding CFS or fatigue in the US is between $18-51 billion [2]. CFS and abnormal fatigue have both been linked to mitochondrial dysfunction [3][4]. The mitochondria are the powerhouse of the human cell and produce ATP, or in other words, Energy. A few major consequences of mitochondrial dysfunction is an increase in free radical production within the cell, elevation of oxidative stress, and lower ATP levels/production [5]. This got me thinking! Can molecular hydrogen improve ATP levels or improve fatigue? What does the research say about this question? First, I want to define what ATP is and then take us through the process in which our cells produce ATP. Second, I want to look at how oxidative stress can disturb the mitochondria or diminish ATP levels. Last, we'll look at how molecular hydrogen may potentially improve and or help to maintain our ATP levels, giving us MORE ENERGY! LET'S GO!

What is ATP: Adenosine triphosphate (C10H16N5O13P3)/molar mass 507.18 g/mol [6]

ATP is a nucleoside triphosphate (NTP) or in other words a nitrogen-based molecule with a phosphate group attached to it. ATP is known as the energy currency of the cell. ATP is used for a multitude of cellular functions including synthesis of proteins, synthesis of membranes, movement of the cell, cellular division, producing ATP, etc. When ATP is broken down into ADP (Adenosine Diphosphate) by the release of Pi (phosphate ion/inorganic phosphate), energy is released. This energy is what drives many cellular functions.

How do human cells (Eukaryotic cells) produce ATP: Cellular Respiration/Glycolysis, fermentation [7]

The human cell can produce ATP one of two ways;  cellular respiration, which requires oxygen (aerobic) and glycolysis which does not require oxygen (anaerobic).

How does cellular respiration (Krebs cycle)/glycolysis work: [8]

Cellular respiration is the primary way our cells produce ATP. This is because cellular respiration yields 32-38 molecules of ATP for each glucose molecule. This process is very efficient. It starts with one glucose molecule and glycolysis in the cell. First, glucose is broken down into two pyruvate molecules or pyruvic acid. This requires an investment of two ATP molecules. The exact mechanism/process to produce the pyruvate molecules starts with two ATP molecules energizing/transferring electrons to glucose forming a 6 carbon diphosphate molecule (fructose-1,6-diphosphate). This molecule will split, and during this phase, the two, 3 carbon molecules will be converted into pyruvate by the interaction with NAD+ producing NADH (NAD+ is a B vitamin pairing with energized electrons and a hydrogen) as a by-product. At the end of this process, 4 ADP interact with the two pyruvate molecules yielding 4 ATP. So, glycolysis requires two ATP and only produces 4 ATP. Glycolysis must first take place in order for cellular respiration to take place. When oxygen is present, the two pyruvate molecules and two NADH molecules will enter into the mitochondria. The Krebs cycle takes place inside of the mitochondria, outside of the intermembrane of the mitochondria. Once the two pyruvate molecules are in the mitochondrial organelle, they will undergo oxidation because pyruvate donates electrons to two NAD+ molecules. This results in two NADH and two Co2 molecules leaving pyruvate converted into two acetyl-CoA molecules. The Krebs cycle/citric acid cycle truly starts at this point. Here, acetyl-CoA will bind with a starting compound called oxaloacetate (4 carbon molecule) which forms the molecule citric acid. This is where a series of enzymatic redox reactions take place. Citric acid interacts with another NAD+ forming NADH and Co2, leaving a 5 carbon molecule (a-ketoglutarate) that interacts with another NAD+ producing another NADH and Co2, leaving a 4 carbon molecule (succinyl-CoA) which reacts with ADP forming ATP, leaving a 4 carbon molecule (succinate) that will go on to react with FAD to form FADH2 and a 4 carbon molecule (fumarate) that interacts with another NAD+ to form NADH leaving the same molecule the cycle started with, oxaloacetate. For every glucose molecule that enters the Krebs cycle, the cycle completes twice, once for each pyruvate molecule. NAD+ and FAD (enzymes) related to B-vitamins (derivatives of Riboflavin and Niacin) that are involved in the cycle are good at holding on to high energy electrons released in the cycle by citric acid and oxaloacetate, which then are released later in the electron transport chain. The net total of molecules produced per one molecule of glucose (two pyruvates) in the cycle is 8 NADH, two FADH2, two ATP, 6 Co2. In order to understand how the rest of the energy is produced by aerobic respiration, you will have to follow the NADH and FADH2 to the electron transport chain.

The electron transport chain is a series of membrane-bound protein complexes. Complex 1 {NADH dehydrogenase}, complex 2 {ubiquinone, succinate reductase}, complex 3 {cytochrome b-c1} complex 4 {cytochrome c}, complex 5 {cytochrome oxidase} located in the mitochondria. These complexes pass electrons from one to another for the production of ATP.  As the NADH and FADH2 give their electrons to ETC, a proton gradient is produced across the intermembrane (the region between the inner membrane and the outer membrane of a mitochondrion). Once the electrons reach the ATP synthesis (protein base complex at the end of the ETC used to form the ATP), the electrons are given to oxygen, the electron acceptor, to form H2O with the H+ that is present. Many free radicals can be produced as by-products of the ETC. At the ATP synthase, protons are pumped back across the intermembrane. When this happens, ADP is squeezed together with some phosphates to form ATP. The 8 NADH from the Krebs cycle can produce 34 ATP through ETC. And two FADH2 produces two ATP each (total of 4 ATP), leading to a possible 38 ATP produced from a single glucose molecule. This is a simple overview breakdown of glycolysis and cellular respiration, as this is a very complex process.

How does Oxidative stress affect ATP production [9][10][11][12]

Oxidative stress can have a profound effect on ATP production and can cause the mitochondria to release apoptotic inducing factor into the cell, triggering cellular death processes. Oxidative stress in the mitochondria can take place because the mitochondria are one of the primary sources of the production of ROS (reactive oxidative species). An increase in ROS can happen for a multitude of reasons including, inflammation, cellular injury, toxins, heavy exercise, bleeding, etc. Once the mitochondria are injured/perturbed, electrons from the ETC can leak. This leakage of electrons produces free radicals like the superoxide anion radicals (●O2-) which can go on to form hydrogen peroxide (H2O2) which then can go to form hydroxyl radicals (●OH), the most cytotoxic radical in the human body. Not all free radicals are bad, and they can, in fact, be beneficial and helpful for the human body. However, when they are in excess, they can cause oxidative stress which has been linked to most, if not all, diseases. One of the main reasons oxidative stress can hurt ATP level is because of the increased levels of H2O2 (hydrogen peroxide). H2O2 in excess can deplete ATP in the mitochondria which can lead to cell death simulation. Oxidative stress can also impair ATP generation by damaging mitochondrial DNA. On the other hand, a moderate decrease in ATP levels as seen in aging/getting older was shown to increase oxidative stress. Nevertheless, maintaining redox homeostasis (oxidative/antioxidant) in cells is critical for ATP levels and cell health.  

Molecular Hydrogen protects ATP production [13]

Molecular hydrogen (H2) has a load of positive benefits for cells and the human body. One of the most documented benefits is the reduction of oxidative stress and bringing the cells back into redox homeostasis when oxidative stress is present. The hydrogen molecule has been shown to have selective antioxidant-like effects, only neutralizing or reducing the cytotoxic free radicals including the hydroxyl radicals (●OH) and peroxynitrite (ONOO–). Molecular hydrogen can also indirectly reduce the levels of hydrogen peroxide in the cells in a number of ways, such as up-regulating of glutathione peroxidase, converting H2O2 into water, and decreasing the activity of NADPH oxidase reducing the generation of H2O2. H2 has great potential for reducing oxidative stress specifically to the mitochondria because of its size (being that molecular hydrogen is the smallest molecule in the universe). H2 is also a neutral molecule, and both of these properties allow molecular hydrogen to have the highest diffusion rate of any molecule or antioxidant. This means H2 can enter all parts of the cell as well as all organelles and the cell's nucleus. So, H2 can enter the mitochondria and reduce oxidative stress, thus increasing mitochondrial efficiency, leading to an increase or maintaining normal ATP production in the thousands of mitochondria in the cell.        

Molecular hydrogen simulates ATP production [14][15]

H2 not only can help to protect the mitochondria from damage or oxidative stress, but there is evidence that H2 was able to stimulate ATP production, even passing the control in some studies. It was shown that H2 can stimulate all the complexes (1-5) in the ETC. This is an extremely important benefit because cells are dependent upon ATP production. This benefit was even shown when the mitochondria were damaged or compromised.    

Molecular Hydrogen might stimulate ATP production independent of the electron transport chain. [16]

Research has brought to light another possible way H2 can stimulate ATP production. H2 might be stimulating ATP production independent of the ETC via Jagendorf reaction (proton gradient produced outside of the ETC). This reaction was first demonstrated by creating an acid environment (high levels of H+ or protons) in the mitochondria which in turn produced ATP without ETC. We have evidence that H2 may do this and can elevate/create ATP independently of the ETC. Further research needs to be on this topic, however, this is possibly another remarkable benefit to H2.

The research in this article only scratches the surface of the many ways molecular hydrogen can potentially increase or maintain your energy levels (ATP levels). The potential for this therapeutic molecule is limitless. To find out more ways H2 can increase your energy levels check out our video entitled Top 5 Ways Molecular Hydrogen Can Boost Your Energy.

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