Dysfunctional Energy Metabolism in Wet Macular Degeneration

Age-related macular degeneration is a condition that causes progressive blindness. The less common wet variety of macular degeneration is characterized by an excessive and damaging growth of blood vessels in the retina. Researchers here map some of the signals and changes that take place in response to dysfunctional energy metabolism in retinal cells, seeing this as a cause of the condition:

Both wet age-related macular degeneration (AMD) and macular telangiectasia are caused by abnormal growth of misshapen, leaky blood vessels in the eye's retina. It's widely believed this growth is triggered by oxygen deprivation. However, new findings suggest another cause: dysfunctional energy metabolism in the eye that starves the retina's light receptors of fuel. Photoreceptors consume a surprising amount of fuel. They have the highest concentration of mitochondria and use more energy than any other cell in the body. They have to be 'on call' all the time to signal light perception and have to recycle their components constantly. Because of this, photoreceptors have evolved a special system to ensure they get enough fuel. While these cells were assumed to be powered by glucose, the study showed that photoreceptors also need lipids, or fats. They have special receptors to take up fatty acids, as well as a special lipid sensor, FFAR1, that curtails glucose uptake when fatty acids are available.

When blood lipids are elevated, the lipid sensor FFAR1 shuts off glucose uptake inappropriately. The energy-starved photoreceptors then call for new blood vessels to bring them nutrients by secreting large amounts of vascular endothelial growth factor (VEGF). This signaling protein is known to encourage abnormal blood-vessel formation in macular disease. VEGF blockers exist and already being used in AMD, but they have systemic side effects, preventing healthy, necessary growth of blood vessels. "If you go upstream of VEGF and solve the energy problem early, it could be more effective and safer." It may be possible to do that by blocking the lipid sensor, FFAR. In experiments where researchers did this, cells were able to keep taking in glucose and the mice had far fewer diseased vessels. The transporter that brings glucose into cells is another potential target, but is harder to reach with drugs, whereas FFAR inhibitors are already in clinical trials for diabetes.

The researchers believe that fuel starvation contributes to age-related macular disease due not only through lack of fuel but also decreased energy efficiency in mitochondria as people age. Abnormal lipid metabolism and mitochondrial dysfunction are both associated with aging and are important risk factors for AMD. The next steps will be to see if people have lipid sensors similar to those in mice. If so, existing inhibitors could be tried in clinical trials.

Link: http://www.eurekalert.org/pub_releases/2016-03/bch-anv031416.php

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