Leaky Membranes in Fragile X Syndrome
Background
Fragile X Syndrome (FXS) is a genetic disorder caused by a mutation in the noncoding region of the fmr1 gene that disables the production of the FMRP protein. Individuals with this mutation have inefficient cellular metabolism which leads to underdeveloped neurons and cognitive deficits. Fragile X is the most common heritable cause of intellectual disability in the world. For more information on FXS, read this review.
Summary: C-sub leaks
In this study, Dr. Jonas and her team discovered why individuals with FXS have such faulty and inefficient metabolisms. Specifically, they found that cells lacking the FMRP protein have leaky mitochondrial membranes. In normal mitochondrial membranes, the ATP synthase protein generates ATP, the primary energy source of the cell. It has two subunits: the membrane embedded region known as the F₀ or c-subunit and the turbine-like region known as F₁. As positive hydrogen ions travel through the c subunit, their motion causes the F₁ region to rotate like a turbine. This rotation causes the conversion of ADP into ATP. If you want to see ATP synthase in action and learn more about its function, this animation is a fantastic resource.
According to this study, the mitochondrial leakage is caused by an imbalance between c-subunit and F₁ levels. In normal individuals, the FMRP protein responds to increases in c-subunit by activating production of more β subunit, a component of the F₁ region. This keeps the amounts of c-subunit and F₁ relatively equal.
But what happens if you don’t have FMRP?
To answer this question, Jonas and her team collected mitochondrial protein samples from both healthy and FXS human brains and analyzed them using a technique called Native PAGE (Featured as our Method of the Month here). The results from this experiment are found in Figure 2B.
The leftmost panel of this figure shows the original Native PAGE gel and the two panels on the right show the data gathered from that gel. According to the graph on the far right, the ratio of free c-subunit to fully assembled ATP synthase protein is three times greater in individuals lacking the fmr1 gene than in normal or wild-type (WT) individuals! This overexpression is extremely problematic for cell metabolism. When these membrane-embedded proteins are on their own, they function as little pores in the mitochondrial membrane, allowing hydrogen ions to pass freely between the inner and outer mitochondrial compartments.
This diffusion of hydrogen ions through free c-subunit is counterproductive for the cell since those ions are not being used to power ATP Synthase. These leaky membranes put considerable metabolic stress on the cells of FXS patients, leading to many of the developmental issues associated with the disease. The closing of these leaky channels may play a significant role in the development of effective FXS therapies.
