Lost genes for metabolic gene therapy
Mitochondria, the power houses of the cell, generate most of the energy needed for all cell processes. Mitochondrial diseases result in devastating, mainly multisystem disorders and are thought to be a result of defects in the mitochondrial oxidative phosphorylation system. Alternative oxidase (AOXs) enzymes form part of additional pathways and are absent in many vertebrates and insects but present in other evolutionary lines. One classic example is the sea squirt, Ciona intestinalis. The ALTERNATIVE OXIDASE (Investigating the roles of the mitochondrial alternative oxidase of Ciona intestinalis) project investigated the pathways that AOX is involved in, what regulates its function and how the enzyme affects organism metabolism. Insights into the alternative respiratory pathways in animals could form the basis for therapies for mitochondrial disorders. Researchers looked at C. intestinalis AOX expression in the fruit fly Drosophila melanogaster. They investigated how nutrition, temperature, and tissue specificity affects development and male competitiveness in these transgenic flies. Limiting carbohydrates reduced adult hatching, eclosion, to a maximum of 35 %. At 29 degree Celsius, on high or zero sugar and high fat diets, there were also problems with eclosion. Results indicate a correlation between low levels of sugar and high fat and low adult hatching rate. Sperm of AOX expressing males as opposed to wild type were defective. During sperm competition in Drosophila, the second male dislodges the first sperm from the female sperm receptacle and replaces it with his own. However, AOX-expressing males do not exhibit this competitive trait as the sperm never leave the testes to be stored in the seminal vesicles. ALTERNATIVE OXIDASE research has shown that AOX expression, when combined with diet and temperature stresses, can affect male fitness. Shown for the first time, research on AOX gene therapies for mitochondrial disorders will have to take into account these possible side-effects.
Keywords
Gene therapy, sea squirt, mitochondrial diseases, mitochondrial oxidative phosphorylation system, AOX
