Abstract:
Cellular respiration is a very essential biochemical process that is heavily researched and understood. The energy synthesizing component of cellular respiration contributes to the importance of studying this biochemical process. Through this paper, an effort is made to project the major mechanisms of respiration along with explaining the components of mitochondria. The paper initially discusses the processes of cellular respiration which includes glycolysis, Kreb’s cycle, and the electron transport chain. Additionally, the glycolysis section of the paper highlights the evolutionary significance of glycolysis. The endosymbiotic theory which proposes the origin of mitochondria within humans is included as well along with the pathologies associated with dysfunctioning mitochondria. Hence, with an aim to review multiple pieces of literature related to cellular respiration, this paper signifies the function of mitochondria and cellular respiration as a complex biochemical reaction that powers human metabolism. Although all living organisms perform cellular respiration, this review paper focuses on human metabolism and metabolic disorders.
Introduction:
Cellular respiration is regarded as an essential metabolic process of biochemistry. This process is fundamental to living beings as this leads to the formation of energy available through the ingestion of food particles. Cellular respiration occurs in all living beings, unlike photosynthesis which happens only in photosynthesizing plants. Photosynthesis is the production of energy through sunlight as a source hence the name. Photosynthesis and cellular respiration are redox reactions where photosynthesis results in an oxidized carbon known as glucose. Whereas cellular respiration results in the reduction of oxygen. This means that in cellular respiration, the electrons are transferred to glucose to produce oxygen. Contrastingly, in photosynthesis, electrons are removed from carbon dioxide to make glucose. Therefore, the reduction-oxidation relationship between these two processes makes them redox reactions. Cellular respiration takes place in different processes based on the evolutionary status of a living being. An anaerobic bacteria can respirate without the presence of oxygen. In this case, any inorganic material like sulfur can replace oxygen to synthesize ATP. Whereas in fermenting bacteria, cellular respiration can occur through the process of fermentation where the byproducts of this process also include lactic acid. Regardless of these differences, glycolysis is an integral process in cellular respiration that seems to occur in all respiring organisms, therefore, proving glycolysis as a beneficial process in evolution. There are many aspects of cellular respiration which are discussed in this review paper. This review paper also discusses the site of cellular respiration which is the mitochondria. Additionally, through various case studies, this paper delineates the mitochondrial diseases that can lead to several medical pathologies.
ATP:
ATP or adenosine triphosphate is the energy molecule in the body. It is produced in the process of cellular respiration. However, it is not used for energy storage like carbohydrates or fats. Instead, they provide energy whenever the body requires it for activities like muscle contraction. The structure of the ATP molecule contains adenosine, ribose sugar, and three phosphate molecules. Thermodynamically, it requires a significant amount of energy to pack three phosphate molecules in a structure. Therefore when the structure breaks through the process of hydrolysis, free energy is released into the body which can be used for body functions. ADP and AMP contain two and one phosphate molecule, respectively. And the amount of free energy released differs based on the number of phosphate molecules present in the structure.
Glycolysis:
Glycolysis is a crucial and first part of cellular respiration. This process is involved in the splitting of 6-carbon glucose molecules to extract energy in the form of the ATP molecule. Glycolysis is regarded as an important and ancient process since all the respiring organisms perform to extract energy. Thus showing the importance of preserving glycolysis throughout the evolutionary events. Glycolysis is a substrate-level phosphorylation process that is divided into two stages which are energy investment and energy-yielding stages. To summarize this complex process, the 6-carbon glucose molecule is broken through hydrolysis to yield a 3-carbon pyruvate sugar.1 Pyruvate is an intermediate that travels to mitochondria for the next steps in cellular respiration.
To initiate the glycolysis events, hexokinase adds a phosphate group to the 6-carbon glucose molecule. This begins the ATP investment stage of the cycle. After the addition of phosphate, the intermediate compound that is produced is known as glucose-6-phosphate (G6P). This molecule is cleaved into 3 carbon sugar by the addition of another phosphate through the phosphofructokinase enzyme that produces the intermediate fructose-1,6-bisphosphate.
After the production of the aforementioned intermediate, the three-carbon molecule or glucose-3-phosphate (G3P) is created to extract energy in the energy extracting phase of the glycolysis. Since 2 ATP molecules are extracted from each G3P molecule, the net yield from the process is 2 ATP. This is because 2 ATP molecules were invested in the ATP investment phase and 4 ATP molecules were extracted from the 2 G3P compounds. A detailed diagram below demonstrates this process.2
Image 1. Events of Glycolysis
Kreb’s Cycle:
Kreb’s cycle is a process that follows glycolysis and takes place in the mitochondrial matrix. Kreb’s cycle is also referred to as the citric acid cycle or the tricarboxylic acid. The pyruvate produced from the glycolysis is transported with the help of oxygen to the mitochondrial matrix for Kreb’s cycle to proceed. Here, the pyruvate is converted to Acetyl-Coenzyme A (Acetyl CoA). Acetyl-CoA reacts further to produce NADH and FADH2 which are useful as electron donors for the next step of cellular respiration known as the electron transport chain. Kreb’s cycle is not only involved in cellular respiration but also in the synthesis of other metabolic products.3 For instance, the production of fatty acids, and amino acids are essential for protein synthesis whereas purines and pyrimidines are essential for nucleic acid synthesis.3 Therefore, Kreb’s cycle is not only essential for cellular respiration but it is also important for synthesizing essential amino and nucleic acids.
Electron Transport Chain:
The process that follows Kreb’s cycle is referred to as the electron transport chain or ETC for short. ETC is an aerobic process that produces water and carbon dioxide as its waste products. Mitochondria is the site for ETC to occur and ETC is the substantial source of ATP produced in the body. ETC is provided its name from the idea that the electrons from the NADH travel down the protein complexes. While traveling down through the protein chain, the electrons are oxidized to release energy. The electrons travel from a series of enzyme centers that help to extract energy from the electrons procured from the NADH/FADH2. The series of enzymes include Complex I, Ubiquinone, Complexes II and III, and cytochrome. The mechanism of extracting energy from these complexes varies. Flavoproteins in complexes I and II help to oxidize FADH2 to FAD+ whereas the Fe atom present in complexes I, II, and III help in the oxidation of NADH to NAD+ by switching from Fe2+ to Fe3+. Through these various mechanisms, the oxidation of electrons becomes possible.4 The hydrogen atom procured from oxidizing electrons that travel down the protein chain is used to power the proton motive force.4
Diffusion of material down the concentration gradient is a passive force; however, diffusion up the concentration gradient requires energy. That energy is available from the ETC. since there is a higher concentration of protons within the mitochondria, exporting it out to the inner membrane space requires energy. And when the proton travels out of the mitochondria, the ATP synthase rotor adds an inorganic phosphate group to the ADP molecule to synthesize ATP. 4 Hence, the energy obtained through the ETC is mentioned as oxidative phosphorylation where the oxidation of electrons delivers energy. Image 2 provides a detailed explanation of the enzymes involved and how the electrons are oxidized in the ETC to obtain energy.6
Image 2. Synthesis of energy in the ETC through the series of proteins present
Image 3. Proton Motive Force is essential for powering the ETC
Mitochondria and the endosymbiont theory:
Mitochondria is a cellular organelle and is the site for the aerobic cellular respiration process. This organelle is responsible for the production of energy. This organelle belongs to the endomembrane system of the cell. However, there is evidence to suggest that this organelle was not originally a part of the eukaryotic cellular respiration process. Mitochondria is surrounded by a double membrane which indicates the first membrane belongs to the host cell whereas the second membrane belongs to the aerobic bacteria ingested through endocytosis by the eukaryotic cell. Moreover, mitochondria possess their own set of genes, a property not seen in other organelles of the endomembrane system. The endosymbiont theory suggests that during the initial evolutionary stage, the eukaryotic cell ingested the alpha-proteobacteria which possessed the ability to respirate aerobically. Due to its evolutionary advantage, this organelle continued to exist in all eukaryotic cells. Therefore this theory indicates how the prokaryotic organelle was transferred to a eukaryotic cell. This theory is also supported by the gene sequencing data which highlights the mitochondrial genome similarity to that of alpha-proteobcateria rather than the host genome. Nevertheless, many mitochondrial genes have been transferred to the host cell nucleus. Thus the major function of this organelle is to produce energy since it has lost its other major functionality. The number of genes contained by mitochondria differs in the species, for example, the human body contains only 13 sets of genes. This number variates for different genes.
ROS:
Reactive oxygen species describes an oxygen molecule that contains one unpaired electron which is extremely reactive. This radical is often a product of metabolism (cellular respiration) or cellular inflammatory defense response. ROS is often associated with aging, cancer, or any other inflammatory diseases. High production of ROS is often triggered by the oxidative stress experienced by the cells. Oxidative stress is defined as a high amount of free radicals and a low amount of antioxidants in the cells. This condition can be triggered by exposure to smoke, inadequate exercise, and unhealthy dietary habits. Due to the presence of incomplete valence electrons, free radicals react relatively rapidly to obtain the electron to stabilize themselves. This reaction is also known as oxidation which is harmful in certain conditions. Antioxidants help this condition by donating an electron to the free radicals without the loss of its stability. 5
Cellular respiration-related pathologies: A case study of Parkinson’s disease:
Cellular respiration is an important process to generate energy in the cells. If there are any mutations that can alter the functioning of this process, can lead to several pathologies. One such case is Parkinson’s disease, a neurodegenerative disease. Previously it was known that a mutation in the genes involved in complex I of the ETC. Nevertheless, current research demonstrates that genes associated with complex III and complex IV are also mutated in the case of PD. These genes are known as the CHCHD and UQCRC1 where the UQCRC1 mutation prevents the release of cytochrome in the ETC. According to Li et. al, it is imperative for the mitochondria to possess functioning quality control genes which include PINK1 and PRKN. It has been reported that the mutations in these quality control genes have caused the early onset of PD. PINK1 is involved in the development of mitochondrial-derived vesicles and when the mitochondria is compromised, then PINK1 is useful for assembling the proteins on the ETC. Therefore, when PINK1 is mutated then there is a high rate of fibroblast degeneration and mitochondrial impairments. Hence, probably contributing to the onset of Parkinson’s disease.7
Cellular respiration-related pathologies: A case study of Fatigue and exercise intolerance:
Throughout this review paper, the role of mitochondria in cellular respiration and energy production is signified. Hence, it is imperative to discuss how mitochondria play a crucial role in high energy expenditure activities like exercising. According to Mancunso et. al, fatigue experienced while performing a rigorous exercise can be an inability to sustain the muscular force. This symptom is commonly observed in mitochondrial disease. Thus, the body depends more on anaerobic respiration which produces lactic acid as a byproduct along with an increased carbon dioxide production.8
Citations
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cellular respiration | Definition, Equation, Cycle, Process, Reactants, & Products | Britannica. (2022). In Encyclopædia Britannica. Retrieved from https://www.britannica.com/science/cellular-respiration
Li, J.-L., Lin, T.-Y., Chen, P.-L., Guo, T.-N., Huang, S.-Y., Chen, C.-H., … Chan, C.-C. (2021). Mitochondrial Function and Parkinson’s Disease: From the Perspective of the Electron Transport Chain. Frontiers in Molecular Neuroscience, 14. https://doi.org/10.3389/fnmol.2021.797833
Mancuso, M., Angelini, C., Bertini, E., Carelli, V., Comi, G. P., Minetti, C., … Siciliano, G. (2012). Fatigue and exercise intolerance in mitochondrial diseases. Literature revision and experience of the Italian Network of mitochondrial diseases. Neuromuscular Disorders, 22, S226–S229. https://doi.org/10.1016/j.nmd.2012.10.012
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