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Oxidative Phosphorylation

Oxidative phosphorylation (OXPHOS) is an essential part of cellular respiration and is the primary metabolic pathway through which cells produce ATP, their main energy molecule. In the mitochondria, OXPHOS utilizes an electron transport chain and a proton gradient to convert ADP into ATP.

Oxidative Phosphorylation

Pathway Summary

Oxidative phosphorylation is the production of ATP using energy derived from the transfer of electrons in an electron transport system and occurs by chemiosmosis. The process is accomplished though oxidation-reduction reactions in the mitochondria. During oxidative phosphorylation, electrons are transferred from electron donors to electron acceptors, referred to as the electron transport chain. The flow of electrons from NADH to O2 through protein complexes located in the mitochondrial inner membrane leads to the pumping of protons out of the mitochondrial matrix. The resulting uneven distribution of protons generates a pH gradient and a transmembrane electrical potential that creates a proton-motive force. ATP is synthesized when protons flow back to the mitochondrial matrix through an enzyme complex (Complex V). The oxidation of fuels and the phosphorylation of ADP are coupled by the proton gradient across the inner mitochondrial membrane.Oxidative phosphorylation consists of five protein-lipid enzyme complexes (Complex I - V) located in the mitochondrial inner membrane that contain flavins (FMN, FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper). These enzymes are designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6. 5.3), complex II (succinate:ubiquinone oxidoreductase, EC 1.3.5.1), complex III (ubiquinol:ferrocytochrome c oxidoreductase, EC 1.10.2.2), complex IV (ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase, EC 1.9.3.1), and complex V (ATP synthase, EC 3.6.1.34). Complex I transports electrons from NADH to ubiquinone. Complex II catalyzes the oxidation of succinate to fumarate and transfers electrons to ubiquinone pool of respiratory chain. Complex III transfers electrons from ubiquinol to cytochrome c coupled with the transfer of electrons across inner mitochondrial membrane. Complex IV, the final step in the electron transport chain, is the reduction of molecular oxygen by electrons derived from cytochrome c. Complex V, the final enzyme in the oxidative phosphorylation pathway, couples a proton gradient generated by respiratory chain to ATP synthesis where protons flow from intermembrane mitochondrial space to the matrix.

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Frequently Asked Questions

What is oxidative phosphorylation (OXPHOS)?

Oxidative phosphorylation, often abbreviated as OXPHOS, is a vital metabolic process that occurs in the mitochondria. It's responsible for producing ATP (adenosine triphosphate), the primary energy molecule for cells, by using an electron transport chain and a proton gradient.

Where does oxidative phosphorylation take place in the cell?
Oxidative phosphorylation primarily takes place in the mitochondria, specifically within the inner mitochondrial membrane. The mitochondria are often referred to as the powerhouses of the cell due to their role in energy production.
How is oxidative phosphorylation related to cellular respiration?
Oxidative phosphorylation is the final stage of cellular respiration. It follows the processes of glycolysis and the citric acid cycle, converting the energy from nutrient molecules into ATP.
What is the role of the electron transport chain in oxidative phosphorylation?
The electron transport chain is a series of protein complexes that transfer electrons from donors to acceptors. This transfer creates a proton gradient across the inner mitochondrial membrane, which is essential for ATP synthesis.
How does the proton gradient contribute to ATP production?
The proton gradient that is established by the electron transport chain provides the necessary energy for a protein called ATP synthase. As protons flow back into the mitochondrial matrix, ATP synthase uses this energy to convert ADP (adenosine diphosphate) and inorganic phosphate into ATP.
Why is oxygen crucial for oxidative phosphorylation?
Oxygen serves as the final electron acceptor in the electron transport chain. It accepts electrons and combines with protons to form water. This step is essential because it ensures that electrons move efficiently through the chain instead of building up and disrupting the energy production process.
How is oxidative phosphorylation regulated within the cell?
Oxidative phosphorylation is intricately regulated by multiple mechanisms to ensure optimal energy production. Feedback loops play a crucial role, where the abundance or scarcity of certain molecules can either promote or inhibit parts of the OXPHOS pathway. In addition, the availability of substrates like NADH (nicotinamide adenine dinucleotide) and FADH2 (flavin adenine dinucleotide) can influence the rate of ATP production. Furthermore, post-translational modifications can activate or deactivate specific components of the OXPHOS system.
Which diseases or conditions are associated with oxidative phosphorylation dysfunction?
Oxidative phosphorylation dysfunction is connected to a variety of health challenges. When the process doesn’t function optimally, cells struggle to produce the energy they require, leading to cellular distress and potential damage. This is evident in neurodegenerative diseases like Parkinson's and Alzheimer's, where the energy-intensive brain cells are compromised. Metabolic disorders, such as mitochondrial myopathies, emerge when muscle cells can't generate enough energy. Furthermore, certain cancers have been found to exhibit changes in OXPHOS activity, which can impact tumor growth and resistance to treatments.
How do cancer cells utilize oxidative phosphorylation?
Many cancer cells, such as those in aggressive forms like glioblastoma or pancreatic cancer, are characterized by increased glycolysis (known as the Warburg effect), but they don't abandon oxidative phosphorylation entirely. Certain cancers, including breast and ovarian cancers, have been observed to retain or even enhance their OXPHOS capabilities under specific conditions. This metabolic flexibility allows them to adapt and thrive in various tumor microenvironments, providing them with a distinct metabolic advantage.
How is oxidative phosphorylation linked to other metabolic pathways?
Oxidative phosphorylation is closely intertwined with metabolic pathways like glycolysis and the citric acid cycle. Glycolysis breaks down glucose to pyruvate, which feeds into the citric acid cycle, generating electron carriers for OXPHOS. Additionally, during low carbohydrate conditions, the body breaks down fats via fatty acid oxidation, producing molecules that also support the citric acid cycle. These integrated pathways ensure consistent energy supply for the cell, adapting to different nutrient sources.

Energy Generation through Oxidative Phosphorylation

Oxidative phosphorylation (OXPHOS) is an essential part of cellular respiration and is the primary metabolic pathway through which cells produce ATP, their main energy molecule. In the mitochondria, OXPHOS utilizes an electron transport chain and a proton gradient to convert ADP into ATP.

Oxidative Phosphorylation and Cellular Energy Production

Oxidative phosphorylation, commonly known as OXPHOS, is a fundamental metabolic pathway that unfolds within the mitochondria, the cellular organelles dedicated to energy production. OXPHOS is the chief method through which cells generate adenosine triphosphate (ATP), the primary molecule that fuels cellular functions. By harnessing the energy derived from the breakdown of nutrients, especially carbohydrates and fats, OXPHOS effectively produces ATP. This intricate process involves a sequence of electron transport events paired with the creation of a proton gradient across the mitochondrial membrane. Given the critical role it plays, OXPHOS is essential for all aerobic organisms, making it a foundational aspect of cellular metabolism.

From Nutrient Breakdown to Proton Gradient

The OXPHOS process begins with the breakdown of nutrients, predominantly glucose. This starts with glycolysis, which converts glucose into pyruvate. The pyruvate then enters the mitochondria, where it undergoes further breakdown in the citric acid cycle. Also known as the Krebs cycle, this series of chemical reactions process pyruvate, producing carbon dioxide and water and releasing energy in the form of NADH (Nicotinamide Adenine Dinucleotide) and FADH2 (Flavin Adenine Dinucleotide). These molecules act as electron carriers, donating their electrons to the electron transport chain (ETC). As electrons are passed from one protein complex to the next in the ETC, they generate energy. This energy is used to actively pump protons (H+ ions) from the mitochondrial matrix into the intermembrane space, establishing a proton gradient across the inner mitochondrial membrane.

Electron Transport Chain: The Heart of OXPHOS

At the core of OXPHOS is the electron transport chain, a series of protein complexes embedded in the inner mitochondrial membrane that transfers electrons from donors to acceptors, producing ATP by driving protons across the membrane to power ATP synthesis. Each of these protein complexes (complex I through complex V) has a unique role in electron transfer and proton translocation. 

Complex I (NADH-ubiquinone oxidoreductase) is the largest complex in the ETC and is responsible for oxidizing NADH to NAD+ and reducing ubiquinone to ubiquinol. During this process, it pumps protons from the mitochondrial matrix to the intermembrane space, contributing to the proton gradient.

Complex II (succinate-ubiquinone oxidoreductase) does not pump protons but instead plays a role in the citric acid cycle by oxidizing succinate to fumarate. At the same time, it reduces ubiquinone to ubiquinol, which is then used by complex III.

Complex III (ubiquinol–cytochrome c oxidoreductase) facilitates the transfer of electrons from ubiquinol to cytochrome c. During this process, it pumps protons from the mitochondrial matrix to the intermembrane space, further contributing to the proton gradient.

Complex IV (cytochrome c oxidase) is responsible for the final step in the electron transport chain. It transfers electrons from cytochrome c to molecular oxygen (O2), producing water. It also pumps protons, enhancing the proton gradient across the inner mitochondrial membrane.

Unlike the other complexes, complex V (ATP synthase) has its primary role in ATP synthesis. Utilizing the proton gradient established by complexes I, III and IV, it drives the synthesis of ATP from ADP and inorganic phosphate as protons flow back into the mitochondrial matrix.

The activity of these complexes isn't static. Research by Shinde and colleagues has shown that external factors, such as the immunostimulatory cytokine TNF-α (tumor necrosis factor-α), can influence the assembly and activity of mitochondrial respiratory chain supercomplexes. By altering the levels of proteins in the supercomplexes, TNF-α promotes metabolic adaptations that favor the survival and proliferation of breast cancer cells.

ATP Synthesis and Oxygen's Role

The culmination of OXPHOS is the production of ATP by the enzyme ATP synthase. As protons flow back into the mitochondrial matrix, driven by their gradient, they release energy, which is used by ATP synthase to convert ADP and inorganic phosphate (Pi) into ATP. A crucial player in this process is molecular oxygen (O2), which acts as the final electron acceptor in the ETC. The combination of oxygen with electrons and protons results in the formation of water. This not only ensures the smooth flow of electrons through the ETC but also prevents their accumulation, which could be detrimental.

Oxygen plays a critical role in OXPHOS, and without sufficient oxygen, the ETC can malfunction, leading to mitochondrial inefficiencies. Such disruptions have been linked to various health conditions. One such example is human atrial fibrillation (AF), where research by Emelyanova and colleagues has shown a decrease in ETC activity affecting complexes I and II and a corresponding rise in oxidative stress, emphasizing oxygen's critical role in mitochondrial and overall cellular health.

Interplay with Other Cellular Processes

OXPHOS doesn't operate in isolation. It's intricately linked with other cellular processes like fatty acid oxidation (beta-oxidation) and amino acid catabolism. During periods of fasting or low carbohydrate intake, the body breaks down fats, leading to the production of acetyl-CoA through beta-oxidation, which then enters the citric acid cycle. Similarly, when proteins are broken down, amino acids can be deaminated and converted into intermediates that feed into the citric acid cycle. Both of these pathways provide alternative sources of NADH and FADH2, ensuring that the ETC remains active even when glucose levels are low. This interconnectedness highlights the cell's ability to adapt its energy production mechanisms based on nutrient availability.

Regulation of OXPHOS

The regulation of oxidative phosphorylation is multifaceted and involves immediate feedback mechanisms, substrate availability, post-translational modifications and longer-term changes in protein expression and membrane composition. This ensures that cells can efficiently produce ATP in response to varying energy demands and environmental conditions. Calcium ions, for instance, enhance the activity of complex IV and complex V of the ETC, acting as a fine tuner of mitochondrial energy production, especially during periods of increased cellular activity like muscle contraction. On the other hand, ATP, when abundant, can inhibit certain steps of OXPHOS, a phenomenon known as feedback inhibition. This ensures that cells don't waste resources producing excess ATP, maintaining energy production in line with cellular demand. Additionally, certain molecules like nitric oxide (NO) can modulate OXPHOS by binding to cytochrome c oxidase.

Upregulation of OXPHOS in Cancers

In many cancers, there is an observed alteration in the expression and function of the OXPHOS machinery. While cancer cells are often characterized by increased glycolysis (known as the Warburg effect), they can still retain functional OXPHOS and might even upregulate it under certain conditions. This upregulation is seen in various cancer types and stages, aiding in cancer cell survival, proliferation and resistance to therapies. The flexibility in using both glycolysis and OXPHOS for energy production provides cancer cells with a metabolic advantage in diverse tumor microenvironments, making OXPHOS a potential therapeutic target.

Further Reading

  1. Boyman L, Karbowski M, Lederer WJ. Regulation of Mitochondrial ATP Production: Ca2+ Signaling and Quality Control. Trends Mol Med. 2020 Jan;26(1):21-39. doi: 10.1016/j.molmed.2019.10.007. 

  2. Emelyanova L et al. Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation. Am J Physiol Heart Circ Physiol. 2016 Jul 1;311(1):H54-63. doi: 10.1152/ajpheart.00699.2015.

  3. Hroudová J, Fišar Z. Control mechanisms in mitochondrial oxidative phosphorylation. Neural Regen Res. 2013 Feb 5;8(4):363-75. doi: 10.3969/j.issn.1673-5374.2013.04.009.

  4. Papa S et al. The oxidative phosphorylation system in mammalian mitochondria. Adv Exp Med Biol. 2012;942:3-37. doi: 10.1007/978-94-007-2869-1_1.

  5. Shinde A et al. TNF-α differentially modulates subunit levels of respiratory electron transport complexes of ER/PR +ve/-ve breast cancer cells to regulate mitochondrial complex activity and tumorigenic potential. Cancer Metab. 2021 Apr 29;9(1):19. doi: 10.1186/s40170-021-00254-9. 

  6. Xu Y, Xue D, Bankhead A 3rd, Neamati N. Why All the Fuss about Oxidative Phosphorylation (OXPHOS)? J Med Chem. 2020 Dec 10;63(23):14276-14307. doi: 10.1021/acs.jmedchem.0c01013.