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The Physiology, in brief

All organ systems are dependent on OXPHOS energy production.  Whether or not organ function occurs depends in part on whether energy production meets a minimum threshold for that organ (below which dysfunction occurs).   Some organs are more highly dependent and may show symptoms even with a relatively small drop in energy production.  For example, the central nervous system has a lower threshold (relative to other organs) at which it will start to show evidence of functional impairment.  Furthermore, energy production over the years of a lifetime becomes less efficient (Wallace, 2001; Navarro, 2007), contributing to why middle-aged adults haven't the same stamina as they did during the teenage years.  It is therefore possible that an affected organ's function might not be compromised early in life but as more of its cells show reduced energy production efficiency over time, evidence of dysfunction will become apparent.

The majority of cases result from abnormalities affecting nuclear-encoded proteins and processes.  These may impact mitochondrial structure and assembly, cofactor transport, the membranes onto which the respiratory components are located, or regulation of mitochondrial DNA (replication, translation) (Di Donato, 2000; DiMauro, 2006).  When mtDNA replication is defective, mtDNA deletions and mtDNA depletion can occur (DiMauro, 2006).

In a minority of cases of mitochondrial disease, the phenotype results from a defect in the maternally-inherited mitochondrial DNA.  In many of these cases, there exist two populations of DNA within the mitochondria of the cell - normal (or wild-type) DNA and mutated (dysfunctional) DNA, a situation termed "heteroplasmy."  Whether or not an organ shows evidence of dysfunction depends in part upon the ratio of normal-to-mutated mtDNA in any given organ (the latter being less effective in generating cellular energy).  If the amount of energy generated falls below a minimum level required for that organ to function, symptoms can occur (threshold effect).  Mitochondria replicate as the cell grows and as energy demands rise; those mitochondria with a higher percentage of mutated DNA do not replicate as well as those with more normal DNA.  Tissues in which cells replicate and divide frequently (like blood cells) may show over time a decrease in the percentage of those cells with higher mutation concentrations (even to the point that it becomes difficult to find any mutated DNA); those cells with normal DNA "out-populate" the others.  However, those tissues that don't show the same turnover (e.g., muscle) will continue to show the persistence of cells with abnormal mitochondrial DNA (and their clinical effects).  That is why testing blood for mtDNA abnormalities may not be as sensitive as evaluating tissue (i.e., muscle).   Whether or not a particular organ shows symptoms depends in part upon whether

Affected siblings or members within the same family can show a wide variation in severity of phenotype.  This is particularly true in disorders caused by defects within the mtDNA; some family members showing evidence of carrying the mutant mtDNA may be severely affected while others show a different (or overlapping) combination of presenting symptoms, while still others appear to be clinically and biochemically asymptomatic.  In part this is due to the random segregation of mutant mitochondria within the original maternal ova; as a fertilized egg divides, the ratio of normal-to-mutant mitochondria varies between the daughter cells.  The resulting cell lines from these daughter cells may have very different energy requirements.  There are likely many other genetic and physiologic factors that influence the impact of the mutant mitochondrial DNA.

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