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Oxidative phosphorylation is a cellular process that harnesses the reduction of oxygen to generate high-energy phosphate bonds in the form of adenosine triphosphate (ATP). It is a series of oxidation-reduction reactions that involve the transfer electrons from NADH and FADH2 to oxygen across several protein, metal, and lipid complexes in the mitochondria known as the electron transport chain (ETC). The electron transport chain utilizes NADH and FADH2 generated from several catabolic cellular processes. Also, oxidative phosphorylation utilizes elemental oxygen as the final oxidizing agent (and electron acceptor). Mitochondrial function and the electron transport chain shed light on the evolution and advancement of aerobic eukaryotic life, especially when compared to anaerobic organisms. It is the hallmark of aerobic respiration and is the reason why a plethora of lifeforms require oxygen to survive.[1][2][3]

A crucially important biochemical process involved in oxidative phosphorylation is the generation of a hydrogen ion gradient between the inner and outer membranes of the mitochondria, also referred to as the chemiosmotic gradient. The energy from this gradient (termed the proton-motive force) is what propels the production of ATP in the mitochondrial matrix. Many molecules have been found to disrupt or impede this process in some way, resulting in both clinical and non-clinical applications. Additionally, dysfunction of the electron transport chain results in a variety of diseases, ranging from metabolic (such as mitochondrial myopathies) to neurological (such as bipolar disorder) in nature. Toxins and Drugs Cyanide and carbon monoxide are known to irreversibly bind to and inhibit protein complex cytochrome c oxidase (complex IV) of the electron transport chain, ceasing the production of ATP and resulting in cell death (and death of the entire organism at high enough concentrations). The sedative amobarbital, while a potent GABA agonist, also binds and inhibits NADH dehydrogenase, resulting in reduced ATP production. Oxidative Stress Reactive oxygen species (ROS) are a byproduct of the electron transport chain complexes that lead to cellular damage via the production and proliferation of free radicals such as peroxides (H2O2) and oxides (such as superoxide). ROS generated from the redox reactions within the four complexes contribute to cell membrane damage and cell senescence. Mitochondrial Myopathy Genetic mutations in mitochondrial DNA (such as MT-ND1) can produce defective complex I (NADH dehydrogenase). This defect will result in reduced production of ATP via oxidative phosphorylation. The macroscopic consequences of this mutation result in a syndrome known as MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). MELAS encephalopathies and myopathies result in symptoms of severe weakness, seizures, and several other symptoms that begin in childhood. Another syndrome known as MERRF (myoclonic epilepsy with ragged red fibers) involves the mutation of a variety of mitochondrial genes, resulting in malformation of many components of the mitochondrion, including the protein complexes of the ETC. The reduced ATP output through oxidative phosphorylation causes many severe clinical symptoms, including myoclonic epilepsy.[14][5][12][15][16]