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