Fight Aging!

There are multiple distinct mechanisms by which cells can generate the energy needed for operations. Since everything is connected to everything else inside a cell, these various mechanisms are also tied in to the regulation of cell behavior, such as whether or not cells are actively assisting in tissue regeneration. Thus ways to change the balance of energy generation in cells might be a viable path towards enhanced regeneration for damaged organs. Researchers here provide evidence for this approach to be useful in the kidney, at least in mice.

Researchers have discovered a pathway for enhancing the self-repair efforts of injured kidneys. This involves reprogramming the body's own metabolism in order to save damaged kidneys. Normally, a process called glycolysis converts glucose from food into energy, which is necessary for life to continue. But the new discovery shows that when tissue is injured, the body can switch the process into one of repair to damaged cells. Researchers found how to intensify the switching process, resulting in a cascade of tissue-repair molecules that successfully stopped progression of kidney disease in mice.

Normally, when cells break down fat, sugars, and proteins into glucose, the three substances are converted into intermediate products that move into the mitochondria, the powerhouse of cells, providing fuel for life. Things work very differently in injured tissues: in the kidneys for example, the body triggers a "Plan B," converting the glucose into new molecules that carry out cell repair instead. Researchers found that a protein called PKM2 controls whether fuel (glucose) is used to power the cell or shift into repair mode. Disabling PKM2 resulted in a significant increase in cell-repair and a concomitant decrease in energy-generation.

A key molecule in the process is nitric oxide (NO). It was already known that NO protects kidneys and other tissue. NO is the active ingredient in nitroglycerine used for addressing heart disease so it was assumed that NO worked by dilating blood vessels. But the research team found that NO attached to a critical molecule called Co-enzyme A - known as a metabolite - linked to the glycolysis and energy production. Co-enzyme A binds to and transports NO into many different proteins, including PKM2, "turning them off." This determines whether the kidney cells are using their pathways for energy or repair.

In addition to finding that adding NO to PKM2 activates repair, researchers found that a protein called AKR1A1 subsequently removes the NO from PKM2, re-activating a robust energy-generating process. This reversal, after healing is complete, allows glucose to be converted efficiently into fuel. When the research team disabled AKR1A1, the kidneys remained in repair mode and were highly protected from disease. Therefore, the goal is to develop drugs to inhibit PKM2 or AKR1A1.

Link: https://www.eurekalert.org/pub_releases/2018-11/cwru-rtb112818.php