Oxidative phosphorylation OXPHOS

Oxidizible substrates from glycolysis, fatty acid or protein catabolism enter the mitochondrion in the form of acetyl-CoA, or as other intermediaries of the Krebs cycle, which resides within the mitochondrial matrix. Reducing equivalents in the form of NADH and FADH pass electrons to complex I (NADH-ubiquinone oxidore-ductase) or complex II (succinate dehydrogenase) of the electron transport chain, respectively. Electrons pass from complex I and II to complex III (ubiquinol-cyto-chrome c oxidoreductase) and then to complex IV (cytochrome c oxidase) which accumulates four electrons and then tetravalently reduces O2 to water. Protons are pumped into the inner membrane space at complexes I, II and IV and then diffuse down their concentration gradient through complex V (FoFi-ATPase), where their potential energy is captured in the form of ATP. In this way, ATP formation is coupled to electron transport and the formation of water, a process termed oxidative phosphorylation (OXPHOS). 

Given the genetic and functional complexity and the fundamental role of mitochondria depicted above, it is not surprising that MRC disorders, or oxidative phosphorylation (OXPHOS) disorders, encompass a huge number of clinical presentations, possibly affecting any of the different body systems. 

A mutation in any of the 13 protein subunits, the 22 tRNAs, or the two rRNAs whose genes are carried in mitochondrial DNA may possibly cause disease. The 13 protein subunits are all involved in electron transport or oxidative phosphorylation. The syndromes resulting from mutations in mtDNA frequently affect oxidative phosphorylation (OXPHOS) causing what are often called "OXPHOS diseases."3-6 Mitochondrial oxidative phosphorylation also depends upon 100 proteins encoded in the nucleus. Therefore, OXPHOS diseases may result from defects in either mitochondrial or nuclear genes. The former are distinguished by the fact that they are inherited almost exclusively maternally. Most mitochondrial diseases are rare. However, mtDNA is subject to rapid mutation, and it is possible that accumulating mutants in mtDNA may be an important component of aging.h k... 

V2. van den Heuvel, L., and Smeitink, J., The oxidative phosphorylation (OXPHOS) system Nuclear genes and human genetic diseases. BioEssays 23, 518-525 (2001). 

When the electron transport system (ETS) and oxidative phosphorylation (OxPhos) are operating,... 

Figure 3. Oxidative phosphorylation (OXPHOS). It is composed by electron transport chain (ETC) and ATP synthase. In ETC, oxidation of reducing equivalents (NADH and FADH2) allow the electron transport from complex I and II to complex III by ubiquinone (violet circle) and from complex III to complex IV by cytochrome -c (pink circle). This process finishes in reduction of molecular oxygen, occurring mitochondrial respiration. Mitochondrial potential membrane (A nn) generated by ETC is used for ATP synthesis by ATP synthase. Adenine nucleotides are transported by voltage-dependent anion channel (VDAC) and adenine nucleotide translocator (ANT).

The primary genetic cause of deficiencies of the oxidative phosphorylation (OXPHOS) system may either be at the mitochondrial DNA (mtDNA) or at the nuclear DNA (nDNA) [5]. In general, mutations of mtDNA can be divided into major rearrangements and point mutations [6, 7]. 

Deficiencies of electron transport In cells, complete transfer of electrons from NADH and FAD(2H) through the chain to O2 is necessary for ATP generation. Impaired transfer through any complex can have pathologic consequences. Fatigue can result from iron-defeciency anemia, which decreases Fe for Fe-S centers and cytochromes Cytochrome Cj oxidase, which contains the O2 binding site, is inhibited by cyanide Mitochondrial DNA (mtDNA), which is maternally inherited, encodes some of the subunits of the electron transport chain complexes and ATP synthase. Oxphos diseases are caused by mutations in nuclear DNA or mtDNA that decrease mitochondrial capacity for oxidative phosphorylation. 

Clinical diseases involving components of oxidative phosphorylation (referred to as OXPHOS diseases) are among the most commonly encountered degenerative diseases. The clinical pathology may be caused by gene mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that encode proteins required for normal oxidative phosphorylation. 

BB, brush border BL, basolateral CYP, cytochrome P450 FA, fatty acid FMO, flavin-containing monooxygenase OA, organic anion OO, organic cation OM, outer medulla OSOM, outer stripe of outer medulla OXPHOS, oxidative phosphorylation PCS, prostaglandin synthase. 

Ischaemic hearts of 7 patients aged 48 to 63 years had increased mtDNA damage and OXPHOS gene expression, suggesting that mtDNA damage is associated with OXPHOS deficiency (Corral-Debrinski et al. 1991). Oxidative phosphorylation defects may also play a role in some other forms of cardiac disease as idiopathic dilated cardiomyopathy, hypertrophic cardiomyopathy, myocarditis, brown atrophy and coronary aAerosclerosis. 

OXPHOS, oxidative phosphorylation NDUF, nuclear-encoded subunits of human complex I Fp, flavoprotein ANT, adenine nucleotide translocase SCO, synthesis of cytochrome c oxidase (assembly gene) COX, cytochrome c oxidase. 

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