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The Biochemistry, in brief

Oxidative phosphorylation (OXPHOS) includes the breakdown of pyruvate through the pyruvate dehydrogenase complex supplying acetyl CoA to the Krebs/tricarboxylic acid cycle.  High-energy electrons are generated and carried by NADH and FADH2 to the electron transport or respiratory chain.  A complex series of reactions produces ATP and water in the presence of oxygen though energy gradients generated at complexes I, III, and IV across complex V.

A defect at any point in energy synthesis can theoretically impact the production of adequate energy for a cell's needs and can be considered a "mitochondrial disorder."  Such a defect is unlikely to be absolute (i.e., "zero" activity for a particular enzyme) since such severe disease is probably not compatible with life (or even embryonic development).  Rather, disorders resulting in dysfunctional oxidative phosphorylation are likely partial enzymatic or functional defects.  Nevertheless they can be associated with very severe phenotypes.  There is no consistent correlation between the severity of a particular biochemical defect and the severity of that patient's phenotype.

The mitochondrion not only houses the biochemical pathways that comprise oxidative phosphorylation but also other metabolic systems, including the proximal half of the urea cycle and fatty acid ?-oxidation which results in ketone production.  As a result, some primary OXPHOS disorders are associated with abnormal intra-organelle environments that impact the normal function of these other chemical pathways.  This can result in "secondary" hyperammonemia (Brown, 1987; Coude, 1981), and/or "secondary" fatty acid oxidation dysfunction with disturbed ketone production (Bennett, 1993; Hagenfeldt, 1998; Enns, 2000); the latter can occur in up to 25% of cases of complex I disease (Shoffner, 2001 - A).

Although primary disorders of the urea cycle and fatty acid ?-oxidation involve enzymes which are located within the mitochondrion, these are not considered primary diseases of energy metabolism (and are not considered in this manual).  It should be noted, however, that these disorders (that involve defective intra-mitochondrial enzymes) can also create an abnormal environment within the mitochondrion and interfere with normal energy synthesis.  In these situations, the mitochondrial dysfunction (and mitochondrial disease-like symptoms those patients might exhibit) is considered a "secondary phenomenon."

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